Pyrozala-pyridyl aminoabkoxyphenol compounds

ABSTRACT

Aminoalkoxyphenyl derivatives useful in the treatment of certain pathological syndromes of the cardiovascular system of formula: ##STR1## in which: B represents a --S--, --SO-- or --SO 2  -- group, 
     R 1  and R 2 , which are identical or different, each denote hydrogen, a methyl or ethyl radical or a halogen, 
     A denotes a straight- or branched-alkylene radical having from 2 to 5 carbon atoms or a 2-hydroxypropylene radical, in which the hydroxy is optionally substituted by a lower alkyl radical, 
     R 3  denotes an alkyl radical or a radical of formula: 
     
         --Alk--R.sub.5 
    
     in which Alk denotes a single bond or a linear- or branched-alkylene radical having from 1 to 5 carbon atoms and R 5  denotes a pyridyl, phenyl, 2,3-methylenedioxyphenyl or 3,4-methylenedioxyphenyl radical or a phenyl group substituted with one or more substituents, which may be identical or different, selected from halogen atoms, lower alkyl groups or lower alkoxy groups, 
     R 4  denotes hydrogen or an alkyl radical or 
     R 3  and R 4  when taken together, denote an alkylene or alkenylene radical having from 3 to 6 carbon atoms and optionally substituted with a phenyl radical or optionally interrupted by --O--, ##STR2## R 6  denoting hydrogen or a lower alkyl or pheny radical, Cy represents a cyclic group with the proviso that when Cy represents a benzo[b]furyl or benzo[b]thienyl group and B represents a --SO 2  -- group, R 3  represents a radical --Alk--R 5 , as well as the N-oxide derivative thereof and a pharmaceutically acceptable salt thereof.

This application is a Division of application Ser. No. 07/495,134, filedMar. 19, 1990, now allowed as U.S. Pat. No. 5039700 which is a divisionof application Ser. No. 07/082,554, filed Aug. 7, 1987, now U.S. Pat.No. 4,957,925, which is a continuation-in-part of application Ser. No.07/006,233, filed Jan. 23, 1987, now abandoned.

The present invention relates to new carbocyclic or heterocyclicderivatives and to a process for preparing them.

More particularly, the invention relates to the novel aminoalkoxyphenylderivatives represented by the general formula: ##STR3## in which: Brepresents a --S--, --SO-- or --SO₂ -- group,

R₁ R₂, which are identical or different, each denote hydrogen, a methylor ethyl radical or a halogen such as chlorine, bromine or iodine,

A denotes a straight- or branched-alkylene radical having from 2 to 5carbon atoms or a 2-hydroxypropylene radical in which the hydroxy isoptionally substituted by a lower alkyl radical,

R₃ denotes an alkyl radical or a radical of formula

    --Alk--R.sub.5

in which Alk denotes a single bond or a linear- or branched-alkyleneradical having from 1 to 5 carbon atoms and R₅ denotes a pyridyl,phenyl, 2,3-methylenedioxyphenyl or 3,4-methylenedioxyphenyl radical ora phenyl group substituted with one or more substituents, which may beidentical or different, selected from halogen atoms, lower alkyl groupsor lower alkoxy groups,

R₄ denotes hydrogen or an alkyl radical, or R₃ and R₄ when takentogether, denote an alkylene or alkenylene radical having from 3 to 6carbon atoms and optionally substituted with a phenyl radical oroptionally interrupted by --O--, ##STR4## R₆ denoting hydrogen or alower alkyl or phenyl radical, Cy represents a group of formula:##STR5## R represents hydrogen, an alkyl radical, a cycloalkyl radical,a benzyl radical or a phenyl radical optionally substituted with one ormore substituents, which may be identical or different, selected fromhalogen atoms, for example fluorine, chlorine, bromine atoms and fromlower alkyl, lower alkoxy or nitro groups,

R₇ and R₈ are taken together with the carbon atom to which they areattached to form:

an optionally aromatic mono- or di-cyclic carbocyclic group having from5 to 10 carbon atoms and optionally substituted by a R group in theα-position with respect to the methyne group,

an optionally aromatic 5-membered heterocyclic group, the heteroatoms orheterogroups being selected from the groups O, S, ##STR6## O and N;##STR7## S and N; ##STR8## N and N; ##STR9## the heterocyclic groupbeing optionally substituted by a R group in the α-position with respectto the methyne group and optionally substituted by one or two groupsselected from lower alkyl and phenyl groups,

an optionally aromatic 6- to 10-membered mono- or di-cyclic heterocyclicgroup, the heteroatoms or heterogroups being selected from the groups O,##STR10## O and N; ##STR11## S and N; ##STR12## N and N; ##STR13## theheterocyclic group being optionally substituted by a R group in theu-position with respect to the methyne group,

R₉ and R₁₀, which are the same or different, each represent hydrogen, alower alkyl radical or a phenyl radical or when they are taken togetherwith the carbon atoms to which they are attached represent an optionallyaromatic 6-membered carbocyclic ring,

R₁₁ represents oxygen or sulphur

R₁₂ represents oxygen, sulphur or a group ##STR14## R₁₃ and R₁₄, whichare identical or different, each represent hydrogen, a lower alkylradical or a benzoyl radical

with the proviso that when Cy represents a benzo[b] furyl or benzo[b]thienyl group and B represents a --SO₂ -- group, R₃ represents a radical--Alk--R₅.

In the present context, both in the description and in the claims, thefollowing meaning attaches to the terms stated above: "alkyl" denotesstraight- or branched-saturated aliphatic hydrocarbon residues having upto 8 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, n-heptyl or n-octyl,"lower alkyl" denotes saturated aliphatic hydrocarbon residues having upto 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl,iso-butyl, tert-butyl or 1-methylpropyl, "lower alkoxy" denotes ahydroxy group substituted with a lower alkyl group as defined above,"cycloalkyl" denotes an alicyclic ring having from 3 to 6 carbon atoms.

Thus, taking into account the meanings given above:

R can denote, in particular, a methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, tert-butyl, 1-methylpropyl, n-pentyl, neopentyl,phenyl, monofluoro-, monochloro- or monobromophenyl, difluoro-,dichloro- or dibromophenyl, monomethyl- or dimethylphenyl, ormonomethoxy- or dimethoxyphenyl radical , a methylphenyl radicalsubstituted with a halogen atom or a cyclopropyl radical,

A can denote, in particular, a 1,2-ethylene, 1,3-propylene,2-methyl-1,3-propylene, 1,4-tetramethylene or 1,5-pentamethylene chain,

R₃ can denote, in particular, a methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, tert-butyl, 1-methyl-propyl, n-pentyl, n-hexyl,n-heptyl, n-octyl, phenyl, benzyl or phenethyl radical, a methoxyphenylor a dimethoxyphenethyl, for example 3,4-dimethoxyphenethyl radical, adimethylphenethyl, dimethoxyphenyl, dimethoxybenzyl or pyridylethylradical or a phenethyl radical substituted in the aromatic portion, withmethyl and methoxy radicals,

R₄ can denote, in particular, a methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, n-heptyl orn-octyl radical,

R₃ and R₄, taken together, can denote, in particular, a1,4-tetramethylene, 1,5-pentamethylene, 3-oxo-1,5-pentamethylene,3-aza-1,5-pentamethylene, 3-methyl-aza-1,5-pentamethylene,3-phenylaza-1,5-pentamethylene or --CH═CH--N═CH-- radical, so that R₃and R₄, taken with the nitrogen atom to which they are attached, candenote, in particular, pyrrolidinyl, piperidyl, morpholinyl,piperazinyl, 4-methylpiperazinyl, 4-phenylpiperazinyl or 1H-imidazolylradical.

Cy can denote, in particular, a phenyl, cyclohexenyl, indenyl, naphthyl,dihydronaphthyl, pyridyl, dihydropyridyl, furyl, dihydrofuryl, thienyl,dihydrothienyl, pyrrolyl, dihydropyrrolyl, pyrazolyl, imidazolyl,pyrimidyl, pyrazinyl, pyridazinyl, oxazolyl, isoxazolyl, thiazolyl,benzofuryl, benzothienyl, indolyl, benzimidazolyl, benzoxazolyl,quinolinyl, benzisoxazolyl, cinnolinyl, quinoxalinyl, quinazolinyl,indolizinyl, thienopyridyl, tetrahydrothienopyridyl, pyrrolopyridyl,pyrazolopyridyl, pyrrolopyridazinyl, imidazopyridyl, dihydrofuranonyl,imidazolinonyl, chromonyl.

A particularly valuable class of compounds of formula I are those inwhich Cy represents an indolizinyl group.

A preferred class of compounds of formula I are those in which Cyrepresents an indolizin-1-yl group.

Another class of compounds of formula I are those in which R₃ representsa group of formula --Alk--R₅.

Particularly useful compounds of formula I are those in which the chain##STR15## represents a [N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy group.

Other valuable compounds of formula I are those in which R represents anisopropyl or cyclopropyl group.

The invention also relates to the pharmaceutically acceptable salts ofthe compounds of formula I formed with an organic or inorganic acid.

As examples of organic salts of this type, there may be mentioned theoxalate, maleate, fumarate, methanesulphonate, benzoate, ascorbate,pamoate, succinate, hexamate, bismethylenesalicylate,ethanedisulphonate, acetate, propionate, tartrate, salicylate, citrate,gluconate, lactate, malate, cinnamate, mandelate, citraconate,aspartate, palmitate, stearate, itaconate, glycolate, p-aminobenzoate,glutamate, benzenesulphonate and theophyllineacetate, as well as thesalts formed with an amino acid such as the lysine or histidine salt.

As examples or inorganic salts of this type, the hydrochloride,hypobromide, sulphate, sulphamate, phosphate and nitrate may bementioned.

Another object of the invention relates to the N-oxide derivatives ofthe compounds of formula I.

The compounds of formula I can exist, in some cases, in the form ofoptical isomers, in particular as a result of the asymetric carbonpresent when A represents a 2-hydroxypropylene chain.

The invention relates, at the same time, to all the isomers of thecompounds of formula I, the isomers being considered in thedextrorotatory or laevorotatory form, or in the form of a mixture, forexample in the form of a racemic mixture.

It has been found that the aminoalkoxyphenyl derivatives of theinvention possess exceptional pharmacological properties, especiallycalcium transport inhibitory properties, as well as bradycardic,hypotensive and antiadrenergic properties.

From this viewpoint, the preferred compounds of the invention are thosein which B represents a --SO₂ -- group.

These properties are capable of making the compounds in question veryuseful on the treatment of certain pathological syndromes of thecardiovascular system, especially in the treatment of angina pectoris,hypertension, arrhythmia and cerebral circulatory insufficiency.

In the antitumour field, the compounds of the invention may be useful aspotentiators of anticancer drugs.

Consequently, the invention also relates to pharmaceutical or veterinarycompositions containing, as active principle, at least oneaminoalkoxyphenyl derivative of formula I or a pharmaceuticallyacceptable salt of this derivative, or an N-oxide derivative thereof, incombination with a pharmaceutical vehicle or a suitable excipient.

Another object of the invention relates to a method for treatingpathological syndromes of the cardiovascular system especially anginapectoris, hypertension, arrhythmia and cerebral vascular insufficiencyin a host in need of such treatment comprising the administration tothis host of an effective dose of an aminoalkoxyphenyl derivative of theinvention.

Depending on the administration route selected, the daily dosage for ahuman being weighing 60 kg will be between 2 and 500 mg of activeprinciple.

The compounds of formula I can be obtained:

I. When B represents a --S-- or --SO₂ -- group and A represents analkylene radical, by condensing, in the presence of an acid acceptor andin a polar solvent such as dimethylsulphoxide or an alcohol, for examplebutanol, or a ketone such as methyl ethyl ketone, or a non-polar solventsuch as an aromatic hydrocarbon, for example benzene, toluene or xylene,a 4-alkoxyphenyl derivative of general formula: ##STR16## in which B'represents a --S-- or --SO₂ -- group, Cy, R₁ and R₂ have the samemeaning as above, A represents an alkylene radical as defined in theformula I and X represents a halogen atom, preferably bromine, or analkylsulphonyloxy group having from 1 to 4 carbon atoms such as forexample, methanesulphonyloxy, or an arylsulphonyloxy group having from 6to 1O carbon atoms, such as benzenesulphonyloxy orp-toluenesulphonyloxy, with an amine of general formula: ##STR17## inwhich R₃ and R₄ have the same meaning as above to form the desiredaminoalkoxyphenyl derivative of formula I in the form of a free base.

In general, the condensation in question is performed at a temperaturebetween room-temperature and the refluxing-temperature of the medium,the acid acceptor being, for example, an alkali metal carbonate orhydroxide or an excess of amine of formula III.

The compounds of formula II in question can be obtained:

a) when X is a halogen, by condensation of a 4-hydroxyphenyl derivativeof general formula: ##STR18## in which Cy, B', R₁ and R₂ have the samemeaning as above, with a dihaloalkane of general formula

    Hal--A--Hal                                                V

in which A denotes an alkylene radical as defined in the formula I andHal denotes a halogen atom, preferably bromine, this reaction beingperformed under reflux in a solvent such as methyl ethyl ketone orN,N-dimethylformamide and in the presence of a basic agent such as analkali metal carbonate, for example potassium carbonate, an alkali metalhydride such as sodium hydride, an alkali metal hydroxide, for examplesodium or potassium hydroxide, or an alkali metal alcoholate, forexample sodium methylate or ethylate,

b) when X denotes an alkylsulphonyloxy or arylsulphonyloxy group, bycondensation of a halide of general formula:

    Hal--W

in which Hal has the same meaning as above and W denotes analkyl-sulphonyl radical having from 1 to 4 carbon atoms, for examplemethanesulphonyl, or an arylsulphonyl radical having from 6 to 1O carbonatoms, for example benzenesulphonyl or p-toluenesulphonyl, in a solventwhich is an acid acceptor, for example pyridine, with a 4-hydroxyalkoxyderivative of general formula: ##STR19## in which Cy, B', R₁ and R₂ havethe same meaning as above and A denotes an alkylene radical as definedin formula I.

As regards the compounds of formula VI, these can be prepared bycondensing, in a suitable solvent such as N,N-dimethylformamide and inthe presence of a basic agent such as an alkali metal carbonate, forexample potassium carbonate, an alkali metal hydroxide such as sodium orpotassium hydroxide, an alkali metal hydride such as sodium hydride oran alkali metal alcoholate, for example sodium methylate or ethylate, a4-hydroxyphenyl derivative of formula IV above with a halogenatedalcohol of general formula:

    Hal--A--OH                                                 VII

in which A denotes an alkylene radical as defined in the formula I andHal has the same meaning as above.

Compounds of formula IV are known products, for instance those compoundsin which Cy represents a benzofuryl or benzothienyl group and B'represents a --SO₂ -- group. These compounds are disclosed in U.S. Pat.No. 4,117,128.

The other compounds of formula IV can be prepared in a generalprocedure, by adapting to the desired compound the method described inthe aforesaid U.S. patent or the methods described hereunder.

In most cases, those compounds of formula IV can be obtained by fixing a4-O-protected benzenesulphonyl or phenylthio chain to the requiredcarbocycle or heterocycle using a Friedel-Crafts reaction anddeprotecting the oxygen in the 4-position of the benzenesulphonyl orphenylthio group by means of classical procedures to regenerate the OHgroup.

Hereunder are examples of methods commonly used for preparingderivatives of formula IV:

Compounds of Formula IV in which Cy Represents a Group (D)

1) The compounds of formula IV in which Cy represents a2-R-indolizin-1-yl group can be prepared from a compound of generalformula: ##STR20## in which B', R, R₁ and R₂ have the same meaning asabove and Y denotes an alkylsulphonyl radical having from 1 to 4 carbonatoms, for example methanesulphonyl, an arylsulphonyl radical havingfrom 6 to 1O carbon atoms, for example benzenesulphonyl orp-toluenesulphonyl, an alkanoyl radical having from 1 to 4 carbon atoms,for example acetyl or Y represents a benzyl or a methyl radical, namely:

by hydrolysis, under reflux and in basic medium when Y denotes analkylsulphonyl, arylsulphonyl or alkanoyl radical,

by hydrogenation using an appropriate catalyst for instance palladiumcharcoal when Y represents a benzyl radical,

by demethylation using an appropriate agent such as pyridinehydrochloride at 180°-220° C. or aqueous hydrobromic acid when Yrepresents a methyl radical.

As regards the compounds of formula VIII, these can be prepared bycyclization under reflux of a picolylsulphone or sulphide of generalformula: ##STR21## in which B', R₁, R₂ and Y have the same meaning asabove, with an α-haloketone of general formula: ##STR22## in which R andHal have the same meaning as above, this being performed in a solventsuch as methyl ethyl ketone and in the presence of a basic agent such asan alkali metal carbonate for example potassium carbonate or an alkalimetal bicarbonate for example sodium bicarbonate.

As regards the picoly sulphones of formula IX, these are obtained byreaction of 2-(chloromethyl)-pyridine of formula: ##STR23## with analkali metal 4-(alkylsulphonyloxy)- or4-(arylsulphinyloxy)benzenesulphinate derivative for example sodium4-(p-toluene-sulphonyloxy)benzenesulphinate according to the processdescribed in J. Chem. Soc. 1965 p. 3090. The derivative of formula XI isa product which is known and which can be prepared by known methods.

As an alternative procedure the compounds of formula IV in which Cyrepresents a 2-R-indolizin-1-yl group and B' represents a --S--group canbe directly obtained from a picolyl sulphide of general formula:##STR24## in which R₁ and R₂ have the same meaning with a α-haloketoneof formula X and cyclising the pyridinium salt so obtained under refluxin a solvent such as water and in the presence of a basic agent such asan alkali metal carbonate for example potassium carbonate or an alkalimetal bicarbonate for example sodium bicarbonate.

The compounds of formula XII are known compounds having been publishedin J. Med. Chem. 26, 218 (1983) or compounds which can be prepared byknown procedures and those of formula IX in which B' represents a--S--group can be obtained from the compounds of formula XII by reactionwith an alkylsulphonyl or arylsulphonyl halide.

2) The compounds of formula IV in which Cy represents a2-R-indolizin-3-yl group can be prepared by reacting an indolizinederivative of general formula: ##STR25## in which R has the same meaningas above and R₁₅ represents a lower alkyl radical preferably ethyl, witha halide of general formula: ##STR26## in which B', R₁, R₂ and Hal havethe same meaning as above and in the presence of a Friedel-Craftscatalyst such as aluminium chloride to provide a compound of generalformula: ##STR27## in which B', R, R₁, R₂ and R₁₅ have the same meaningas above.

The compound of formula XV is subsequently demethylated using anethanethiol/aluminium chloride mixture to give a 4-methoxyphenylderivative of general formula: ##STR28## in which B', R, R₁ and R₂ havethe same meaning as above which, when heated to about 200° C. providesthe required compound of formula IV.

The compounds of formula XIII are either known compounds having beenpublished in J. Chem. Soc. 1962 pp. 2627-2629 or compounds which can beprepared in accordance with the method described therein.

3) The compounds of formula IV in which Cy represents a2-R-imidazo[1,2-a]pyrid-3-yl group can be prepared from a2-R-imidazo[1,2-a]pyridine with a halide of formula XIV and in thepresence of a Friedel-Crafts catalyst such as aluminium chloride toprovide a compound of general formula: ##STR29## in which B', R, R₁ andR₂ have the same meaning as above.

The compound of formula XVII is subsequently demethylated using anappropriate agent for instance hydrobromic acid or anethanethiol/aluminium chloride mixture to give the required compound offormula IV.

2-Aryl-imidazo[1,2-a]pyridines are known from J. Med. Chem. 8, p. 305(1965). The other 2-R-imidazo[1,2-a]pyridines can be obtained inaccordance with the method described in the aforesaid reference or usingclassical procedures.

4) The compounds of formula IV in which Cy represents a pyridyl or3-R-4-pyridyl group can be obtained by demethylating with an appropriateagent such as aqueous hydrobromic acid, a 4-methoxyphenyl derivative ofgeneral formula: ##STR30## in which B', R₁ and R₂ have the same meaningas above and R has the same meaning as above with the exception ofhydrogen, to provide the required compounds of formula IV.

The compounds of formulae XVIII and XVIII' in which B' represents a--SO₂ -- group can be prepared by oxidizing a sulfide derivative ofgeneral formula: ##STR31## in which R₁ and R₂ have the same meaning asabove and R has the same meaning as in formula XVIII or XVIII'.

Compounds of formula XIX are known having been described in U.S. Pat.No. 4,128,552. The other compounds of formula XIX can be obtained inaccordance with the method described in the aforesaid U.S. patent whilethose compounds of formula XIX' can be prepared from a 3-R-pyridine, inwhich R is other than hydrogen, by oxidation with hydrogen peroxide inacetic acid to provide the corresponding 3-R-pyridine-N-oxide which whenreacted with a nitric acid/sulphuric acid mixture gives rise to thecorresponding 3-R-4-nitro-pyridine-N-oxide.

This nitro derivative is then reacted first with acetyl bromide, thenwith iron powder in acetic acid to give the corresponding3-R-4-bromo-pyridine which, when treated with a thiophenol derivative ofgeneral formula: ##STR32## in which R₁ and R₂ have the same meaning asabove and M represents an alkali metal atom such as sodium, provides therequired compound of formula XIX'.

5) The compounds of formula IV in which Cy represents a2-R-quinolin-3-yl group can be prepared by reacting an α-haloketone offormula X with a metal derivative of general formula: ##STR33## in whichM, B', R₁ and R₂ have the same meaning as above and Ts represents ap-toluenesulphonyl group, to provide a ketone of general formula:##STR34## in which B', R, R₁, R₂ and Ts have the same meaning as above.

This ketone of formula XXII when treated with 2-amino-benzaldehyde[Helv. Chem. Act. vol. XVIII, p. 1235 (1935)]gives the 4-methoxyphenylderivative of general formula: ##STR35## in which B', R, R₁, R₂ and Tshave the same meaning as above, which is subsequently hydrolysed inbasic medium for instance in aqueous alkali metal hydroxide, to providethe required compound of formula IV.

The compounds of formula IV in which Cy represents a 3-R-cinnolin-4-ylor 4-R-cinnolin-3-yl group can be obtained by reacting a3-R-4-halogenocinnoline (J. Chem. Soc. 1953, p. 609) with a thiophenolderivative of general formula: ##STR36## in which M, R₁, R₂ and Ts havethe same meaning as above and B' represents a --S-- group to provide the4-tosyloxyphenyl derivative of general formula: ##STR37## in which R,R₁, R₂ and Ts have the same meaning as above and B' represents a --S--group.

The 4-tosyloxyphenyl derivative of formula XXV or XXV' is subsequentlyhydrolysed in basic medium for instance in aqueous alkali metalhydroxide to give the required compound of formula IV in which B'represents a --S-- group. Compounds of formula XXIV in which --OTs isreplaced by --OCH₃ can also be used. In such case the correspondingcompound of formula XXV or XXV' is demethylated using for instancehydrobromic acid.

The sulphide derivative of formula XXV or XXV' when oxidized with asuitable agent such as hydrogen peroxide in acetic acid or potassiumpermanganate, provides the compound of formula XXV or XXV' in which B'represents a --SO₂ -- group, which compound after hydrogenation on acatalyst such as palladium charcoal or platinum charcoal gives therequired compounds of formula IV in which B' represents a --SO₂ --group.

Alternatively the compounds of formula IV in question in which B'represents a --SO₂ -- group can be obtained from a3-R-4-halogenocinnoline or a 4-R-3-halogeno-cinnoline by reacting with abenzenesulphonyl derivative of general formula XXIV in which B'represents a --SO₂ -- group to obtain a compound of formula XXV or XXV'in which B' represents a --SO₂ -- group which is detosylated asdescribed above to provide the required compound of formula IV.

7) The compounds of formula IV in which Cy represents a 6-R-pyrrolo[1,2-b]pyridazin-5-yl group can be prepared by reacting a3-halogenomethylpyridazine with a metal derivative of formula XXI toprovide a pyridazine derivative of general formula: ##STR38## in whichB', R₁, R₂ and Ts have the same meaning as above, which is subsequentlyreacted with an c-haloketone of formula X in the presence of anon-nucleophilic base such as for example 1,8-diazabicyclo[5,4,0]undec-7-ene to give the pyrrolo [1,2-b]pyridazine derivative of generalformula: ##STR39## in which B', R, R₁, R₂ and Ts have the same meaningas above.

The tosyl derivative of formula XXVII is then hydrolysed in a basicmedium for instance aqueous alkali metal hydroxide, to provide therequired compound of formula IV.

3-Chloromethyl-pyridazine is a known compound having been published inKhim. Geterot. Sikl. Soedin. 3, pp. 412-414 (1970).

8) The compounds of formula IV in which Cy represents a 2-R-pyrazolo[1,5-a]pyrid-1-yl group can be prepared, in accordance with the methoddescribed in European patent application No. 121, 197, by treating a2-R-pyrazolo[1,5-a]pyridine with a halide of formula XIV in the presenceof a Friedel-Crafts catalyst such as for example aluminium chloride, toprovide the 4-methoxyphenyl derivative of general formula: ##STR40## inwhich B', R, R₁ and R₂ have the same meaning as above.

The pyrrolopyridine derivative of formula XXVIII is then demethylatedfor instance by using pyridine hydrochloride at 200°-220° C. to providethe required compound of formula IV.

9) The compounds of formula IV in which Cy represents a phenyl group canbe prepared by reacting benzene with a halide of formula XIV in thepresence of a Friedel-Crafts catalyst such as aluminium chloride, toprovide the required compound of formula IV.

10) The compounds of formula IV in which Cy represents a 2-R-phenylgroup or a 1-R-2-naphthyl group can be prepared by treating a halide ofgeneral formula: ##STR41## in which B', R and Hal have the same meaningas above and R₉ and R₁₀ each represent hydrogen or are taken togetherwith the carbon atom to which they are attached to form a phenyl group,with a methoxyphenyl derivative of general formula: ##STR42## in whichR₁ and R₂ have the same meaning as above, in the presence of aFriedel-Crafts catalyst such as aluminium chloride, to obtain thecompounds of general formula: ##STR43## in which B', R, R₁ and R₂ havethe same meaning as above and R₉ and R₁₀ have the same meaning as informula XXIX.

The compounds of formula XXXI are then demethylated using for instanceaqueous iodhydric acid to provide the required compound of formula IV.

Compounds of formula XXIX are known products having been described inC.A. 81, 63285 g, or can be obtained in accordance with knownprocedures.

11) The compounds of formula IV in which Cy represents an optionallymono- or di-substituted 2-R-4,5-dihydro-furan-3-yl group can be preparedby heating a ketone derivative of formula XXII with a1,2-dihalogenoethane of general formula: ##STR44## in which R₁₆ and R₁₇,which are the same or different, each represent hydrogen, a lower alkylradical or a phenyl radical, in the presence of a basic agent such as analkali metal carbonate, to obtain a cyclopropane derivative of generalformula: ##STR45## in which B', R, R₁, R₂, R₁₆, R₁₇ and Ts have the samemeaning as above.

The cyclopropane derivative of formula XXXIII is subsequently heatedbetween 100° and 130° C. in the presence of a phase transfer catalystsuch as for instance triphenylphosphine or tricaprylylmethyl ammoniumchloride to provide a 4-tosyloxyphenyl derivative of general formula:##STR46## in which B', R, R₁, R₂, R₁₆, R₁₇ and Ts have the same meaningas above and the said 4-tosyloxyphenyl derivative is then detosylated bytreatment with a basic agent such as an alkali metal hydroxide, toprovide the required compound of formula IV.

12) The compounds of formula IV in which Cy represents an optionallymono- or di- substituted 2-R-furan-3-yl group can be obtained byoxidizing for instance with manganese oxide, a 4,5-dihydrofuranderivative of formula XXXIV to obtain a furan derivative of generalformula: ##STR47## in which B', R, R₁, R₂, R₁₆, R₁₇ and Ts have the samemeaning as above, which furan derivative is subsequently treated with abasic agent such as an alkali metal hydroxide, to obtain the requiredcompound of formula IV.

13) The compounds of formula IV in which Cy represents a 2-R-furan-3-ylor 2-R-thien-3-yl or 2-R-pyrrol-3-yl group can be prepared by reacting acompound of general formula: ##STR48## in which R has the same meaningas above and Q represents O, --S or ##STR49## with a halide of formulaXIV and in the presence of a Friedel-Crafts catalyst such as aluminiumchloride to obtain a 4-methoxy derivative of general formula: ##STR50##in which B', R, R₁, R₂ and Q have the same meaning as above, which issubsequently decarboxylated by heating and demethylated with anappropriate agent such as pyridine hydrochloride or aqueous hydrobromicacid, to provide the required compound of formula IV.

Alternatively, the compounds of formula IV in which Cy represents anoptionally substituted 2-R-furan-3-yl group can be prepared byoxidizing, for instance with manganese oxide, a 4-tosyloxyphenylderivative of formula XXXIV to obtain an optionally substituted2-R-3-(4-tosyloxybenzenesulphonyl)furan derivative which is subsequentlytreated by a basic medium for instance an alkali metal hydroxide, toprovide the required compound of formula IV.

The compounds of formula IV in which Cy represents a 1-R-imidazol-2-ylor 1-R-benzimidazol-2-yl group can be obtained by reacting a1-R-imidazole or 1-R-benzimidazole with a halide of formula XIV in thepresence of a Friedel-Crafts catalyst such as aluminium chloride, toobtain a compound of general formula: ##STR51## in which B', R, R₁ andR₂ have the same meaning as above, R₉ and R₁₀ each represent hydrogen orare taken together with the carbon atoms to which they are attached toform a phenyl group and Bz represents a benzyl group, which issubsequently debenzylated using for instance palladium charcoal toobtain the required compound of formula IV.

When R represents hydrogen, imidazole or benzimidazole is protected inthe 1-position with an appropriate N-protecting group for instance abenzyl group which can subsequently be removed, if desired, usingclassical procedures.

15) The compounds of formula IV in which Cy represents an optionallysubstituted 5-R-isoxazol-4-yl derivative can be prepared by reacting anisoxazole derivative of general formula: ##STR52## in which B', R, R₁₆and Hal have the same meaning as above with a 4-methoxy derivative offormula XXX in the presence of a Friedel-Crafts catalyst such asaluminium chloride to obtain the compounds of general formula: ##STR53##in which B', R, R₁, R₂ and R₁₆ have the same meaning as above, which isoptionally demethylated, to provide the required compound of formula IV.

Compounds of formula XXXIX are known products having been described inGazz. Chim. Ital. 76, 30 (1946) while the other compounds of formulaXXXIX can be obtained in accordance with the method described therein orclassical methods.

16) The compounds of formula IV in which B' represents a SO₂ -- groupand Cy represents a group of formula (D) in which R₇ and R₈ are takentogether with the carbon atom to which they are attached to form a nonaromatic mono- or di-cyclic carbocyclic group having from 5 to 10 carbonatoms and optionally substituted by a R group in the α-position withrespect to the methyne group, for instance a 3-R-inden-2-yl,2-R-cyclohexen-1-yl or 1-R-3,4-dihydro-naphth-2-yl group can beprepared, in accordance with the method described in J. Org. Chem., vol.35, No. 12, pp. 4217-4222 (1970) by heating a compound of generalformula: ##STR54## in which R₇ and R₈ are taken together with the carbonatom to which they are attached to form a group having from 5 to 10carbon atoms and optionally substituted by a R group in the α-positionwith respect to the methyne group, with a halide of formula XIV in anappropriate solvent such as benzene and in the presence of anhydrouscupric chloride and triethylamine, to obtain a 4-tosyloxyphenylderivative of general formula: ##STR55## in which R₁, R₂ and Ts have thesame meaning as above and R₇ and R₈ have the same meaning as in formulaXXXXI which is then detosylated using an appropriate agent such as analkali metal hydroxide to obtain the required compound of formula IV.

b) Compounds of Formula IV in which Cy Represents a Group (E)

The compounds of formula IV in which Cy represents a 2-R-imidazol-yl or2-R-benzimidazol-1-yl group can be obtained by reacting a 2-R-imidazoleor 2-R-benzimidazole with a halide of formula XIV in the presence of aFriedel-Crafts catalyst such as aluminium chloride, to provide acompound of general formula: ##STR56## in which B', R, R₁ and R₂ havethe same meaning as above and R₉ and R₁₀ each represent hydrogen or aretaken together with the carbon atoms to which they are attached to forma phenyl group.

The compound of formula XXXXIII is then demethylated using anappropriate agent for instance an ethanethiol/aluminium chloride mixtureto give the required compound of formula IV.

c) Compounds of Formula IV in which Cy Represents a Group (F)

The compounds of formula IV in which Cy represents for instance a2-R-chromon-3-yl group and B' represents a --SO₂ -- group can beprepared by reacting a 2-R-3-halogeno-chromone with a 4-methoxyderivative of formula XIV in which B' represents a --SO₂ -- group, inthe presence of a Friedel-Crafts catalyst such as aluminium chloride, toobtain the chromone derivative of general formula: ##STR57## in which R,R₁ and R₂ have the same meaning as above, which is optionallydemethylated using for instance aqueous hydrobromic acid or pyridinehydrochloride, to provide the required compound of formula IV.

d) Compounds of Formula IV in which Cy Represents a Group (G)

The compounds of formula IV in which Cy represents an optionallysubstituted 5-R-2,3-dihydro-furan-2-one-4-yl can be prepared byreacting, in basic medium, for instance potassium carbonate, a ketone offormula XXII with a 2-halogenoacetate of general formula: ##STR58## inwhich Hal, R₁₅ and R₁₆ have the same meaning as above, to obtain aketoester which is first hydrolysed in basic medium and then treatedwith a strong acid to provide the carboxylic acid derivative of generalformula: ##STR59## in which B', R, R₁, R₂ and R₁₆ have the same meaningas above.

The acid of formula XXXXVI when treated with trifluoroacetic acid orthionyl chloride provides the required compound of formula IV.

e) Compounds of Formula IV in which Cy Represents a Group (H)

The compounds of formula IV in which Cy represents an optionallysubstituted 5-R-1,3-dihydro-2H-imidazol-2-one-4-yl can be obtained byreacting a 5-R-imidazol-2-one with a halide of formula XIV to obtain acompound of general formula: ##STR60## in which R, R₁, R₂, R₁₃, R₁₄ andB' have the same meaning as above which is subsequently demethylatedusing appropriate procedures such as in the presence of iodhydric acid,pyridine hydrochloride or hydrobromic acid, to obtain the requiredcompound of formula I.

As an alternative procedure, the compounds of formula IV in question canbe prepared by adapting the method similar to that described in J. Am.Chem. Soc. 68, p. 2350 (1946).

According to an alternative method, the compounds of formula I in whichB represents a --S-- or --SO₂ -- group and A represents an alkyleneradical, preferably those in which A represents a propylene radical, canalso be obtained by reacting, in the presence of a basic agent such asan alkali metal carbonate, for example potassium carbonate, an alkalimetal hydroxide such as sodium or potassium hydroxide, an alkali metalhydride such as sodium hydride or an alkali metal alcoholate, forexample sodium methylate or ethylate, a 4-hydroxyphenyl derivative offormula IV above with a compound of general formula: ##STR61## in whichX has the same meaning as above and preferably represents chlorine or abenzenesulphonyl or p-toluenesulphonyl radical, A represents an alkyleneradical and R₃ and R₄ have the same meaning as above, the reactiontaking place at a temperature between room-temperature and the refluxingtemperature of the medium and in a polar solvent such as methyl ethylketone or dimethylsulphoxide to form the desired aminoalkoxyphenylderivative of formula I in the form of the free base.

When R₄ represents hydrogen, the nitrogen atom is preferably protectedby a labile group for instance a protecting group which can beeliminated in basic medium for example the tertiobutoxycarbonyl (BOC)group.

The compounds of formula XXXXVIII are products which are known or whichcan be prepared by known methods.

The compounds of formula I in which Cy represents a group (E), Arepresents an alkylene chain and B represents a --S-- or --SO₂ -- groupcan also be prepared by reacting a 2-R-imidazole or 2-R-benzimidazolewith a halide of general formula: ##STR62## in which B', R₁, R₂, Hal andX have the same meaning as above and A represents an alkylene chain, inthe presence of an acid acceptor such as triethylamine to obtain acompound of general formula: ##STR63## in which B', R, R₁, R₂ and X havethe same meaning as above, R₉ and R₁₀ each represent hydrogen or aretaken together with the carbon atom to which they are attached to form aphenyl group and A represents an alkylene chain, which compound issubsequently reacted with an amine of formula III to obtain the requiredcompound of formula I in the form of a free base.

Similarly, the compounds of formula I in which Cy represents anoptionally mono- or di- substituted 2-R-4,5-dihydro-furan-3-yl group, Arepresents an alkylene chain and B represents a --S-- or --SO₂ -- group,can be prepared by hydrolysing a cyclopropane derivative of formulaXXXII in the presence of an aqueous alkali metal hydroxide solution toprovide a 4-methoxyphenyl derivative of general formula: ##STR64## inwhich B', R, R₁, R₂, R₁₆ and R₁₇ have the same meaning as above, whichis then reacted:

with a dihaloalkane of formula V and the resulting product with an amineof formula III or

with a compound of general formula XXXXVIII, to provide anaminoalkoxyphenyl derivative of general formula: ##STR65## in which B',R, R₁, R₂, R₃, R₄, R₁₆ and R₁₇ have the same meaning as above and Arepresents an alkylene chain.

The cyclopropane derivative of formula (LII) is subsequently heatedbetween 100° and 130° C. in the presence of a phase transfer catalystsuch as for instance triphenylphosphine or tricaprylylmethyl ammoniumchloride to provide the required 2,3-dihydrofuran derivative of formulaI in the form of a free base.

II. When B represents a --SO-- group, by treating, with an oxidizingagent, a sulphide of formula I in which B represents a --S-- group, thiscompound of formula I being in the form of the free base of a saltthereof so as to obtain the required compound in the form of the freebase or a salt thereof.

Where the required compound is provided in the form of a salt, the freebase thereof can be recovered by treatment with a basic agent such as analkali metal carbonate for example potassium carbonate or an alkalimetal bicarbonate for example sodium bicarbonate.

Generally, the reaction takes place in water or in an organic solventsuch as methylene chloride and in the presence of a suitable oxidizingagent such as for example sodium periodate, potassium permanganate or3-chloroperbenzoic acid.

Depending on the oxidizing agent used, mixtures of sulphoxides orsulphones can be obtained. These mixtures can be separated byconventional procedures for instance by chromatography.

III. When B represents a --S-- or --SO₂ -- group and A represents anoptionally substituted 2-hydroxy-propylene chain, by reacting underreflux a 4-hydroxyphenyl derivative of formula IV with an epihalohydrin,such as epichlorhydrin or epibromhydrin in dextrorotatory orlaevorotatory form or in the form of a mixture of these isomers, forexample in racemic form, and in the presence of a basic agent such as analkali metal carbonate, for example potassium carbonate, an alkali metalhydroxyde, for example sodium or potassium hydroxide, an alkali metalhydride, such as sodium hydride or an alkali metal alcoholate, forexample sodium methylate of ethylate, and in a polar solvent such asmethyl ethyl ketone to give the oxiranylmethoxy derivatives of generalformula: ##STR66## in which Cy, B, R, R₁ and R₂ have the same meaning asabove.

The oxyranylmethoxy derivatives of formula (LIII) are then treated underreflux with an amine of formula III, this being performed in a polarsolvent such as methyl ethyl ketone or in an excess of amine of formulaIII to give the desired compound of formula I in the form of the freebase in which A represents a 2-hydroxypropylene chain which can bereacted, if desired, with a lower alkyl halide in the presence of astrong base to provide the compound of formula I in the form of the freebase in which A represents a 2-hydroxypropylene chain in which thehydroxy is substituted by a lower alkyl radical.

In some cases, by-products may be formed in parallel with the compoundsof formula (LIII) above, on this case4-(3-halo-2-hydroxypropoxy)benzenesulphonyl derivatives.

On reaction with the amine of formula III, these derivatives willnevertheless give rise to the desired compounds of formula I in which Arepresents a 2-hydroxypropylene chain.

The compounds of formulae II, IV, VI and XIV in which Cy represents anindolizin-1-yl group together with the compounds of formula VIII are newintermediate compounds.

In consequence, they constitute another subject of the invention.

Overall, these particular compounds of formulae II, IV, VI, VIII and XIVcan be represented by the general formula: ##STR67## in which B', R, R₁and R₂ have the same meaning as above and Z denotes hydrogen, anoxiranylmethyl radical, an alkylsulphonyl radical having from 1 to 4carbon atoms, an arylsulphonyl radical having from 6 to 10 carbon atomsor a radical of formula:

    --A--Z.sub.1

in which A denotes a linear- or branched-alkylene radical having from 2to 5 carbon atoms and Z₁ denotes a halogen atom, a hydroxy radical, analkylsulphonyloxy radical having from 1 to 4 carbon atoms or anarylsulphonyloxy radical having from 6 to 1O carbon atoms.

The compounds of formula I thereby obtained in the form of the free basecan then be converted to pharmaceutically acceptable salts by reactionwith a suitable organic or inorganic acid, for example oxalic, maleic,fumaric, methanesulphonic, benzoic, ascorbic, pamoic, succinic, hexamic,bismethylenesalicylic, ethanedisulphonic, acetic, propionic, tartaric,salicylic, citric, gluconic, lactic, malic, cinnamic, mandelic,citraconic, aspartic, palmitic, stearic, itaconic, glycolic,p-aminobenzoic, glutamic, benzenesulphonic or theophyllineacetic acid orwith lysine or histidine.

Similarly, the N-oxide derivatives of the compounds of formula I can beformed by oxidizing the compound of formula I in question with anappropriate oxidizing agent for instance hydrogen peroxide or3-chloroperbenzoic acid.

Monoalkyl- or dialkylaminoalkoxybenzenesulphonyl-benzofuran orbenzothiophene derivatives are reported in U.S. Pat. No. 4,117,128 aspresenting pharmacological effects in the cardiovascular field.

In the course of the elaboration of the present invention, tests werecarried out with compounds specifically cited in the aforesaid U.S.patent, more particularly with 2-ethyl- or2-n-butyl-3-[4-(2-diethylaminoethoxy)benzenesulphonyl]benzofuran.

From results of these tests, it could be concluded that in the dog atthe dose of 10 mg/kg by intravenous route, these known compounds onlypresent a weak α-antiadrenergic activity and no or practically noβ-antiadrenergic effect.

It has now been surprisingly discovered, in the context of the presentinvention, that by replacing the mono- or di-alkylaminoalkoxy chain ofthe benzenesulphonyl-benzofurans or benzothiophenes of the prior art byan aralkylaminoalkoxy chain, compounds are obtained which show muchgreater α- and β-antiadrenergic activities than those of the knowncompounds in question.

For instance, aralkylaminoalkoxybenzenesulphonyl-benzofurans orbenzothiophenes in question have shown, at doses as low as 0.1 to 1.5mg/kg, sub-total inhibition of the α-adrenergic effect together with animportant β-antiadrenergic action.

Such very valuable antiadrenergic properties were also found to bepresent in compounds similar in structure to thearalkylaminoalkoxybenzenesulphonyl-benzofurans and benzothiophenes inquestion but in which the benzofuran or benzothiophene moiety isreplaced by another carbocyclic or heterocyclic group.

Therefore, one class of compounds of the invention relates to thosecompounds of formula I and the pharmaceutically acceptable salts orN-oxide thereof, in which Cy, R₁, R₂, R₄ and A have the same meaning asin formula I, B represents a --SO₂ -- group and R₃ represents a radical--Alk--R₅.

A particularly valuable class of compounds of the invention are those inwhich R₁, R₂, R₄ and A have the same meaning as in formula I, Brepresents a --SO₂ -- group, R₃ represents a radical --Alk--R₅, Cyrepresents a group selected from:

indolizinyl more particularly 2-R-indolizin-1-yl and 2-R-indolizin-3-yl

benzofuryl or benzothienyl more particularly 2-R-benzofur-3-yl and2-R-benzothien-3-yl

quinolinyl such as 2-R-quinolin-3-yl

pyrrolo[1,2-b]pyridazinyl more particularly 6-R-pyrrolo[1,2-b]pyridazin-5-yl

pyrazolo[1,5-a]pyridyl more particularly 2-R-pyrazolo[1,5-a]pyrid-3-yl

imidazo[1,2-a]pyridyl more particularly 2-R-imidazo[1,2-a]pyrid-3-yl

4,5-dihydrofuranyl more particularly 2-R-3,4-dihydrofuran-3-yl group.

Similarly indolizine derivatives which are substituted in the 1-positionwith an alkyloxybenzoyl chain which is itself substituted with a mono-or di-alkyl amino group, and which are stated to have pharmacologicaleffects in the cardiovascular field, are already known.

In this connection, there may be mentioned French Patent No. 2,341,578and Eur. J. Med. Chem. 1977, 12, No. 4 pp. 345-350, which specificallydescribe 2-ethyl-, 2-n-propyl- or 2-n-butyl-1-[4-(3-di-n-propyl- or3-di-n-butylaminopropoxy)benzoyl]indolizine optionally dimethylated onthe benzoyl radical.

These known compounds showed antiadrenergic activities which werenon-existent or low, at all events too low to be of any value fortherapy.

Other monoalkyl- or dialkyl-aminoalkoxybenzoyl derivatives are alsoknown.

For instance are reported in the literature monoalkyl- ordialkyl-amino-benzoyl derivatives of:

thiophene [(J. Med. Chem. V, 13 (3) pp. 359-366 (1970)]

naphthalene or dihydronaphthalene (Chim. Ther. V, 7 (5) pp. 369-377)

pyridine [Ing. Chim. V, 59 (283) pp. 3-3 (1977)]

thieno[3,2-c]pyridine [Heterocycles, V, 22 (5), pp. 1235-1247 (1984)]

indole [Eur. J. Med. Chem.--Chim. Ther. V, 12 (5) pp. 483-487 (1977)]

furan (French patent No. 2,400,515)

chromone (U.S. Pat. No. 4,220,645).

Tests carried out with these known compounds showed that same of thempresented antiadrenergic activities but which were low, at all eventstoo low to be of any value for therapy.

It has now been found, in addition, that mono- or di-alkylaminoalkoxybenzenesulphonyl derivatives ressembling those described in U.S. Pat.No. 4,117,128 but in which the benzofuran or benzothiophene moiety hasbeen replaced by another carbocyclic or heterocyclic ring present morevaluable antiadrenergic properties than known sulphonyl derivatives ofthe aforesaid U.S. patent or known benzoyl derivatives of theabove-cited references.

For instance, α- and β-antiadrenergic properties were registered, in thedog by intravenous route at doses as low as 0.1 to 1.5 mg/kg withrespect to mono- or di-alkylaminoalkoxybenzenesulphonyl derivatives offormula I in which Cy represents another group than benzofuryl orbenzothienyl for instance a quinolinyl or pyrrolo[1,2-b]pyridazinylmoiety.

Yet, another valuable class of compounds of the invention are those inwhich R₁, R₂, R₄ and A have the same meaning as in formula I, Brepresents a --SO₂ -- group and R₃ represents an alkyl radical with theproviso that Cy is different from benzo[b]furyl or benzo[b]thienyl.

A particularly valuable class of compounds of the invention are those inwhich R₁, R₂, R₄ and A have the same meaning as in formule I, Brepresents a --SO₂ -- group, R₃ represents an alkyl radical and Cyrepresents a group selected from:

quinolinyl more particularly 2-R-quinolin-3-yl

pyrrolo[1,2-b]pyridazinyl more particularly 6-R-pyrrolo[1,2-b]pyridazin-5-yl.

pyrazolo[1,5-a]pyridyl more particularly 2-R-pyrazolo[1,5-a]pyrid-3-yl.

imidazo[1,2-a]pyridyl more particularly 2-R-imidazo[1,2-a]pyrid-3-yl.

4,5-dihydrofurannyl more particularly 2-R-4,5-dihydrofuran-3-yl group.

Moreover, it has been found that the calcium inhibitory activity of thecompounds of the invention is at least equal to, if not greater than,that observed in tests performed with the known compounds. In contrastto the known compounds, it has thus been possible to demonstrate for thecompounds of the present invention a pharmacological spectrum revealinganticalcium and α- and β-antiadrenergic components with a balancedintensity which is of therapeutic value, for example, for treatment ofangina.

As has been reported in detail by R. Charlier in "Bruxelles Medical",No. 9, September 1969, pages 543-560, it is accepted than an antianginaldrug treatment should be capable, in particular, of antagonizing theantiadrenergic type cardiovascular reactions. To this end, agentscapable of blocking the α-receptors have been proposed.

However, the clinical application of such compounds to the treatment ofangina remained unsuccessful, very probably due to the fact thatβ-receptor antagonists induce only a very partial neutralization of theadrenergic system, the activity of the β-receptors being unaffected.

In fact, the most undesirable haemodynamic manifestations which occur inangina pectoris patients during their painful attacks are, most of all,cardiac, and consequently involve the β-receptors.

In parallel, treatments have been proposed with drugs which areβ-adrenergic receptor antagonists. These compounds, which are of genuineclinical value, decrease the attacks of angina by reducing the work ofthe heart by slowing the heart rate. However, there is no fall in theperipheral arterial resistance which, on the contrary, rises throughrelease of the α-tonicity.

These drug treatments nevertheless modify some haemodynamic parametersin a direction which, at a fundamental level, detracts from the value ofthese drugs for angina pectoris patients in particular and heartpatients in general.

If the antiadrenergic aspect of β-blockers is considered, it becomesclear that only the tachycardia and the increase in the force and thespeed of contraction of the heart are capable of being neutralized, thearterial hypertension involving a stimulation of the α-receptors onwhich β-antagonists have no action.

In fact, while the cardiovascular disturbances brought about by thestimulation of the β-receptors are the more harmful to angina patients,it is nonetheless true that arterial hypertension also plays a notinsignificant part.

In addition, blocking the β-receptors involves a risk, depriving thepatient suffering from cardiac insufficiency of a compensatory mechanismwhich he normally brings into play to limit his circulatoryinsufficiency.

This reflex mechanism, the main component of which makes use of thepathway of the β-adrenergic system, leads, in particular, to an increasein the force and the speed of contraction of the heart. In consequence,if this system is blocked, the patient suffering from cardiacinsufficiency experiences a worsening of his functional breakdown. It ishence logical to consider that the use of a β-blocker whose action ispure and complete will always involve a cardiac risk.

It hence appears to be desirable not to seek complete α- orβ-antagonistic properties, given the clinical side effects that thesecan bring about. It seems more logical to aim to subdue rather than toeliminate the cardiovascular disturbances which characterize thehyperstimulation of the adrenergic system as a whole.

The compounds of the invention meet this objective since they showincomplete α- and β-type antiadrenergic properties. They can hence beconsidered, not as β-blockers but as adreno-decelerators, that is to saypartial antagonists of the α- and β-adrenergic reactions, potentiallydevoid of the disadvantages listed above for β-blockers.

In addition, the calcium inhibitory component demonstrated in thecompounds of the invention will act as an exceptional complement to thepharmacological spectrum of their cardiovascular action.

It is known, in effect, that the transport of calcium ions is one of themain components of the action potential in heart cells and, inconsequence, this transport plays a fundamental part in the electricalconduction as well as in the disorders which may occur therein(arrhythmia). In addition, it is known that calcium ions are involved inthe excitation-contraction coupling which controls the degree ofvasoconstriction in smooth muscle and, in the same circumstances, playsa critical part in attacks of angina pectoris.

Compounds which are calcium antagonists act at the level of the cellmembrane by selectively preventing calcium from participating in theprocess of contraction within the arterial cell.

In fact, it appears increasingly clear, at the present time, that theclinical results provided by the Z5 combination of calcium inhibitorsand β-adrenergic inhibitors are better than when each inhibitor is usedseparately (J.A.M.A. 1982, 247, pages 1911-1917).

It appears, moreover, that no β-blocker which exerts, in addition, asignificant inhibitory action in respect of calcium transport exists atthe present time.

From this standpoint, the compounds of the invention possessing both ananticalcium component and an α- and β-antiadrenergic component will beof fundamental value, since they are capable of more extensivetherapeutic applications than a separate β-blocker or a separate calciuminhibitor. By way of example, the following may be mentioned:

2-ethyl-1-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]indolizine(EX. 28)

2-isopropyl-1-{4-[3-(di-n-butylaminooropyloxy]benzenesulphonyl}indolizine (Ex.1)

2-ethyl-1-{4-[3-(di-n-butylamino)propyloxy)benzenesulphonyl}indolizine(Ex.8), and

2-isopropyl-1-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]indolizine(Ex. 30)

which possess an α- and β-antiadrenergic component reinforced by anoxygen-economizing effect capable of providing a therapeutic effect inman in the syndrome of angina of effort, which can, moreover, be treatedby traditional β-blockers. However, the major advantage of thesecompounds will reside in the fact that they may, as a result of theiranti-calcium effect, be used in the treatment of angina at rest, asyndrome induced by the appearance of a spasm in the coronary arteries,which is combated at present by compounds such as diltiazem, verapamilor nifedipine.

In addition, compounds of the invention were also shown to be capable ofinducing a substantial increase in the coronary flow.

The results of pharmacological tests performed for the purpose ofdetermining the cardiovascular properties of the compounds of theinvention are recorded

I. CALCIUM INHIBITORY PROPERTIES

The properties of inhibiting calcium transport at the membrane levelshown by the compounds of the invention were demonstrated by measuringtheir antagonistic action with respect to the contractile response topotassium-induced depolarization on isolated rat aorta. It is wellestablished that the depolarization of a smooth muscle membrane bypotassium renders the latter permeable to extracellular calcium andinduces muscle contraction.

Consequently, the measurement of the inhibition of the contractileresponse to depolarization by potassium, or the measurement of arelaxation of the tonic contraction on potassium depolarization, canrepresent an evaluation of the power of a compound as an inhibitor ofthe membrane permeability to Ca⁺⁺ ions.

The technique used was as follows:

The aorta was removed from male Wistar rats weighing approximately 300g, and cut into strips approximately 40 mm long and 3 mm wide.

These fragments were placed in a 25-ml isolated organ trough containinga modified Krebs-bicarbonate solution (112 mM NaCl; 5 mM KCl; 25 mMNaHCO₃ ; mM KH₂ PO₄ ; 1.2 mM MgSO₄ ; 2.5 mM CaCl₂ ; 11.5 mM glucose,distilled water to 1000 ml) through which a stream of 5-7% carbondioxide in oxygen was passed, and maintained at 37° C. The preparationwas connected to a force microsensor and the contractile responserecorded after amplification on a recorder.

A tension of 2 g was applied to the preparation. This tension wasmaintained for 60 minutes in the modified Krebs-bicarbonate solution,and contractions were then induced by replacing the Krebs-bicarbonatesolution by a potassium-Krebs solution (17 mM NaCl; 100 mM KCl; 25 mMNaHCO₃ ; 1 mM KH₂ PO₄ ; 1.2 mM MgSO₄ ; 2.5 mM CaCl₂ ; 11.5 mM glucose;distilled water to 1000ml). When the contractile response of thepreparation had become reproducible, a given amount of a compound of theinvention was introduced into the bath. Sixty minutes later, a new spasmwas induced by potassium depolarization.

The results obtained on the aorta used in the experiment were thenexpressed as a percentage of the maximum contractional effect beforeincubation with the test substance.

By way of examples, the results which follow were obtained, thecompounds of formula I being in the form of the base, hydrochloride oroxalate. ##STR68##

    __________________________________________________________________________                                                        % of the maximum          Compound                                                                            R           R.sub.1                                                                           R.sub.2                                                                           n  Am                     contractional             __________________________________________________________________________                                                        effect                    a) At a dose of 10.sup.-6 M                                                   Ex. 12                                                                              n-C.sub.4 H.sub.9                                                                         H   H   3  N(n-C.sub.3 H.sub.7).sub.2                                                                           36.3                      Ex. 13                                                                              n-C.sub.4 H.sub.9                                                                         H   H   3  N(n-C.sub.4 H.sub.9).sub.2                                                                           39.8                      Ex. 29                                                                              n-C.sub.4 H.sub.9                                                                         H   H   3  NHC(CH.sub.3).sub.3    30.7                      Ex. 18                                                                                          H   H   3  N(n-C.sub.4 H.sub.9).sub.2                                                                           55.6                      Ex. 19                                                                               ##STR69##  CH.sub.3                                                                          H   3  N(n-C.sub.4 H.sub.9).sub.2                                                                           77.2                      Ex. 24                                                                               ##STR70##  H   H   3  NHC(CH.sub.3).sub.3    62.1                      Ex. 25                                                                               ##STR71##  H   CH.sub.3                                                                          3  NHC(CH.sub.3).sub.3    67.7                      Ex. 21                                                                              C.sub.2 H.sub.5                                                                           H   H   3  NH(n-C.sub.4 H.sub.9)  8.3                       Ex. 20                                                                              C.sub.2 H.sub.5                                                                           H   H   3  N(CH.sub.3)(n-C.sub.4 H.sub.9)                                                                       6.8                       Ex. 10                                                                              C.sub.2 H.sub.5                                                                           CH.sub.3                                                                          CH.sub.3                                                                          3  N(n-C.sub.4 H.sub.9).sub.2                                                                           2.9                       Ex. 4 CH.sub.3    H   H   3  N(C.sub.2 H.sub.5).sub.2                                                                             77.2                      Ex. 5 CH.sub.3    H   H   3  N(n-C.sub.3 H.sub.7).sub.2                                                                           48.9                      Ex. 6 CH.sub.3    H   H   3  N(n-C.sub.4 H.sub.9).sub.2                                                                           13.9                      Ex. 7 C.sub.2 H.sub.5                                                                           H   H   3  N(n-C.sub.3 H.sub.7).sub.2                                                                           8.3                       Ex. 9 C.sub.2 H.sub.5                                                                           CH.sub.3                                                                          H   3  N(n-C.sub.4 H.sub.9).sub.2                                                                           17.4                      Ex. 3 C.sub.2 H.sub.5                                                                           H   H   3  NHC(CH.sub.3).sub.3    30.7                      Ex. 2 C.sub.2 H.sub.5                                                                           H   H   3                                                                                 ##STR72##             22.6                      Ex. 11                                                                        n-C.sub.3 H.sub.7                                                                   H           H   3   N(n-C.sub.4 H.sub.9).sub.2                                                       8.8                                              Ex. 14                                                                              CH(CH.sub.3).sub.2                                                                        H   H   3  N(CH.sub.3).sub.2      32.6                      Ex. 15                                                                              CH(CH.sub.3).sub.2                                                                        H   H   3  N(C.sub.2 H.sub.5).sub.2                                                                             18.4                      Ex. 17                                                                              CH(CH.sub.3).sub.2                                                                        H   H   3  N(n-C.sub.3 H.sub.7).sub.2                                                                           7.4                       Ex. 1 CH(CH.sub.3).sub.2                                                                        H   H   3  N(n-C.sub.4 H.sub.9).sub.2                                                                           2.0                       Ex. 31                                                                              CH(CH.sub.3).sub.2                                                                        H   H   3                                                                                 ##STR73##             16.8                      Ex. 32                                                                              CH(CH.sub.3).sub.2                                                                        H   H   3                                                                                 ##STR74##             3.6                       Ex. 33                                                                              CH(CH.sub.3).sub.2                                                                        H   H   3                                                                                 ##STR75##             24.6                      Ex. 34                                                                              CH(CH.sub.3).sub.2                                                                        H   H   3                                                                                 ##STR76##             3.3                       Ex. 35                                                                              CH(CH.sub.3).sub.2                                                                        H   H   3                                                                                 ##STR77##             8.3                       Ex. 36                                                                              CH(CH.sub.3).sub.2                                                                        H   H   3  N(n-C.sub.8 H.sub.17).sub.2                                                                          83.3                      Ex. 44                                                                              CH(CH.sub.3).sub.2                                                                        H   H   3                                                                                 ##STR78##             29.8                      Ex. 51                                                                               ##STR79##  H   H   3  N(n-C.sub.4 H.sub.9).sub.2                                                                           58.9                      b) At a dose of 10.sup.-7 M                                                   Ex. 21                                                                              C.sub.2 H.sub.5                                                                           H   H    3 NH(n-C.sub.4 H.sub.9)  74.7                      Ex. 20                                                                              C.sub.2 H.sub.5                                                                           H   H   3  N(CH.sub.3)(n-C.sub.4 H.sub.9)                                                                       60.0                      Ex. 10                                                                              C.sub.2 H.sub.5                                                                           CH.sub.3                                                                          CH.sub.3                                                                          3  N(n-C.sub.4 H.sub.9).sub.2                                                                           49.0                      Ex. 22                                                                              C.sub.2 H.sub.5                                                                           H   H   2  N(n-C.sub.4 H.sub.9).sub.2                                                                           37.0                      Ex. 23                                                                              C.sub.2 H.sub.5                                                                           H   H   4  N(n-C.sub.4 H.sub.9).sub.2                                                                           24.1                      Ex. 26                                                                              C.sub.2 H.sub.5                                                                           H   H   3  N(n-C.sub.5 H.sub.11).sub.2                                                                          42.9                      Ex. 6 CH.sub.3    H   H   3  N(n-C.sub.4 H.sub.9).sub.2                                                                           69.1                      Ex. 7 C.sub.2 H.sub.5                                                                           H   H   3  N(n-C.sub.3 H.sub.7).sub.2                                                                           60.0                      Ex. 8 C.sub.2 H.sub.5                                                                           H   H   3  N(n-C.sub.4 H.sub.9).sub.2                                                                           30.9                      Ex. 9 C.sub.2 H.sub.5                                                                           CH.sub.3                                                                          H   3  N(n-C.sub.4 H.sub.9).sub.2                                                                           57.2                      Ex. 2 C.sub.2 H.sub.5                                                                           H   H   3                                                                                 ##STR80##             79.8                      Ex. 11                                                                        n-C.sub.3 H.sub.7                                                                   H           H   3   N(n-C.sub.4 H.sub.9).sub.2                                                       37.7                                             Ex. 15                                                                              CH(CH.sub.3).sub.2                                                                        H   H   3  N(C.sub.2 H.sub.5).sub.2                                                                             71.2                      Ex. 17                                                                              CH(CH.sub.3).sub.2                                                                        H   H   3  N(n-C.sub.3 H.sub.7).sub.2                                                                           50.4                      Ex. 1 CH(CH.sub.3).sub.2                                                                        H   H   3  N(n-C.sub.4 H.sub.9).sub.2                                                                           18.9                      Ex. 16                                                                              C(CH.sub.3).sub.3                                                                         H   H   3  N(n-C.sub.4 H.sub.9).sub.2                                                                           35.8                      Ex. 27                                                                              C.sub.2 H.sub.5                                                                           H   H   3                                                                                 ##STR81##             7.7                       Ex. 28                                                                              C.sub.2 H.sub.5                                                                           H   H   3                                                                                 ##STR82##             14.2                      Ex. 30                                                                              CH(CH.sub.3).sub.2                                                                        H   H   3                                                                                 ##STR83##             9.4                       Ex. 31                                                                              CH(CH.sub.3).sub.2                                                                        H   H   3                                                                                 ##STR84##             31.8                      Ex. 32                                                                              CH(CH.sub.3).sub.2                                                                        H   H   3                                                                                 ##STR85##             19.4                      Ex. 33                                                                              CH(CH.sub.3).sub.2                                                                        H   H   3                                                                                 ##STR86##             57.6                      Ex. 34                                                                              CH(CH.sub.3).sub.2                                                                        H   H   3                                                                                 ##STR87##             28.1                      Ex. 35                                                                              CH(CH.sub.3).sub.2                                                                        H   H   3                                                                                 ##STR88##             25.0                      Ex. 36                                                                              CH(CH.sub.3).sub.2                                                                        H   H   3  N(n-C.sub.8 H.sub.17).sub.2                                                                          93.7                      Ex. 38                                                                              C.sub.2 H.sub.5                                                                           H   H   3                                                                                 ##STR89##             85.9                      Ex. 37                                                                              CH(CH.sub.3).sub.2                                                                        H   H   3  N(n-C.sub.5 H.sub.11).sub.2                                                                          48.7                      Ex. 39                                                                              CH(CH.sub.3).sub.2                                                                        H   H   4  N(n-C.sub.4 H.sub.9).sub.2                                                                           17.9                      Ex. 40                                                                              C.sub.2 H.sub.5                                                                           H   H   5  N(n-C.sub.4 H.sub.9).sub.2                                                                           49.7                      Ex. 41                                                                              CH(CH.sub.3).sub.2                                                                        H   H   3                                                                                 ##STR90##             5.3                       Ex. 46                                                                              CH(CH.sub.3).sub.2                                                                        H   H   3                                                                                 ##STR91##             4.3                       Ex. 47                                                                              CH(CH.sub.3).sub.2                                                                        H   H   3                                                                                 ##STR92##             17.9                      Ex. 44                                                                              CH(CH.sub.3).sub.2                                                                        H   H   3                                                                                 ##STR93##             78.9                      Ex. 43                                                                              CH(CH.sub.3).sub.2                                                                        H   H   3                                                                                 ##STR94##             9.7                       Ex. 42                                                                              CH(CH.sub.3).sub.2                                                                        H   H   4                                                                                 ##STR95##             21.1                      Ex. 45                                                                              CH(CH.sub.3).sub.2                                                                        H   H   3                                                                                 ##STR96##             18.7                      Ex. 51                                                                               ##STR97##  H   H   3  N(n-C.sub.4 H.sub.9).sub.2                                                                           80.4                      c) At a dose of 10.sup.-8 M                                                   Ex. 10                                                                              C.sub.2 H.sub.5                                                                           CH.sub.3                                                                          CH.sub.3                                                                          3  N(n-C.sub.4 H.sub.9).sub.2                                                                           82.6                      Ex. 22                                                                              C.sub.2 H.sub.5                                                                           H   H   2  N(n-C.sub.4 H.sub.9).sub.2                                                                           90.2                      Ex. 23                                                                              C.sub.2 H.sub.5                                                                           H   H   4  N(n-C.sub.4 H.sub.9).sub.2                                                                           77.8                      Ex. 26                                                                              C.sub.2 H.sub.5                                                                           H   H   3  N(n-C.sub.5 H.sub.11).sub.2                                                                          82.9                      Ex. 1 CH(CH.sub.3).sub.2                                                                        H   H   3  N(n-C.sub.4 H.sub.9).sub.2                                                                           61.0                      Ex. 16                                                                              C(CH.sub.3).sub.3                                                                         H   H   3  N(n-C.sub.4 H.sub.9 ).sub.2                                                                          78.7                      Ex. 27                                                                              C.sub.2 H.sub.5                                                                           H   H   3                                                                                 ##STR98##             58.9                      Ex. 28                                                                              C.sub.2 H.sub.5                                                                           H   H   3                                                                                 ##STR99##             60.2                      Ex. 30                                                                              CH(CH.sub.3).sub.2                                                                        H   H   3                                                                                 ##STR100##            40.1                      Ex. 31                                                                              CH(CH.sub.3).sub.2                                                                        H   H   3                                                                                 ##STR101##            73.9                      Ex. 32                                                                              CH(CH.sub.3).sub.2                                                                        H   H   3                                                                                 ##STR102##            65.9                      Ex. 33                                                                              CH(CH.sub.3).sub.2                                                                        H   H   3                                                                                 ##STR103##            87.0                      Ex. 34                                                                              CH(CH.sub.3).sub.2                                                                        H   H   3                                                                                 ##STR104##            82.6                      Ex. 35                                                                              CH(CH.sub.3).sub.2                                                                        H   H   3                                                                                 ##STR105##            65.6                      Ex. 37                                                                              CH(CH.sub.3).sub.2                                                                        H   H   3  N(n-C.sub.5 H.sub.11).sub.2                                                                          77.8                      Ex. 39                                                                              CH(CH.sub.3).sub.2                                                                        H   H   4  N(n-C.sub.4 H.sub.9).sub.2                                                                           62.9                      Ex. 40                                                                              C.sub.2 H.sub.5                                                                           H   H   5  N(n-C.sub.4 H.sub.9).sub.2                                                                           87.9                      Ex. 41                                                                              CH(CH.sub.3).sub.2                                                                        H   H   3                                                                                 ##STR106##            26.1                      Ex. 46                                                                              CH(CH.sub.3).sub.2                                                                        H   H   3                                                                                 ##STR107##            49.5                      Ex. 47                                                                              CH(CH.sub.3).sub.2                                                                        H   H   3                                                                                 ##STR108##            69.6                      Ex. 44                                                                              CH(CH.sub.3).sub.2                                                                        H   H   3                                                                                 ##STR109##            89.5                      Ex. 43                                                                              CH(CH.sub.3).sub.2                                                                        H   H   3                                                                                 ##STR110##            58.4                      Ex. 42                                                                              CH(CH.sub.3).sub.2                                                                        H   H   4                                                                                 ##STR111##            53.9                      Ex. 45                                                                              CH(CH.sub.3).sub.2                                                                        H   H   3                                                                                 ##STR112##            62.3                      d) At a dose of 10.sup.-9 M                                                   Ex. 27                                                                              C.sub.2 H.sub.5                                                                           H   H   3                                                                                 ##STR113##            81.6                      Ex. 28                                                                              C.sub.2 H.sub.5                                                                           H   H   3                                                                                 ##STR114##            85.4                      Ex. 30                                                                              CH(CH.sub.3).sub.2                                                                        H   H   3                                                                                 ##STR115##            81.7                      Ex. 41                                                                              CH(CH.sub.3).sub.2                                                                        H   H   3                                                                                 ##STR116##            70.9                      Ex. 46                                                                              CH(CH.sub.3).sub.2                                                                        H   H   3                                                                                 ##STR117##            78.1                      Ex. 47                                                                              CH(CH.sub.3).sub.2                                                                        H   H   3                                                                                 ##STR118##            86.5                      Ex. 43                                                                               CH(CH.sub.3).sub.2                                                                       H   H   3                                                                                 ##STR119##            88.7                      Ex. 42                                                                              CH(CH.sub.3).sub.2                                                                        H   H   4                                                                                 ##STR120##            78.8                      Ex. 45                                                                              CH(CH.sub.3).sub.2                                                                        H   H   3                                                                                 ##STR121##            80.7                      __________________________________________________________________________     ##STR122##                                                                                                        % of the maximum contractional                                                effect                                   Compound                                                                            R        Am                    10.sup.-6 M                                                                          10.sup.-7 M                                                                         10.sup.-8 M                                                                          10.sup.-9            __________________________________________________________________________                                                             M                    Ex. 49                                                                              CH(CH.sub.3).sub.2                                                                     N-(n-C.sub.4 H.sub.9).sub.2                                                                         5.4    12.8  67.6   80.2                 Ex. 50                                                                              CH(CH.sub.3).sub.2                                                                      ##STR123##           4.6    6.6   44     78                   __________________________________________________________________________     ##STR124##                                                                                                              % of the maximum contractional                                                effect                             Compound                                                                            B"    R       Am                     10.sup.-5 M                                                                        10.sup.-6 M                                                                        10.sup.-7 M                                                                        10.sup.-8           __________________________________________________________________________                                                              M                   Ex. 52                                                                              S     CH(CH.sub.3).sub.2                                                                    N-(n-C.sub.4 H.sub.9).sub.2                                                                          69.2 81.2 --   --                  Ex. 53                                                                              S     CH(CH.sub.3).sub.2                                                                     ##STR125##            59.8 75.4 --   --                  Ex. 54                                                                              SO    CH(CH.sub.3).sub.2                                                                    N-(n-C.sub.4 H.sub.9).sub.2                                                                          --   --   74.3 82.4                __________________________________________________________________________     ##STR126##                                                                                                              % of the maximum contractional                                                effect                             Compound                                                                            Cy              Am                   10.sup.-6 M                                                                        10.sup.-7 M                                                                        10.sup.-8 M                                                                        10.sup.-9           __________________________________________________________________________                                                              M                   Ex. 74                                                                               ##STR127##     N9n-C.sub.4 H.sub.9).sub.2                                                                         22.4 67.3 --   --                  Ex. 75                                                                               ##STR128##                                                                                    ##STR129##          3.7  54   89.7 --                  Ex. 70                                                                               ##STR130##     N(n-C.sub.4 H.sub.9).sub.2                                                                         0    18.9 83   --                  Ex. 71                                                                               ##STR131##                                                                                    ##STR132##          0    15.1 67.1 84.9                Ex. 72                                                                               ##STR133##     NHC(CH.sub.3).sub.3  13.2 66.5 84   --                  Ex. 76                                                                               ##STR134##                                                                                    ##STR135##          --   0    18.1 68.1                Ex. 63                                                                               ##STR136##                                                                                    ##STR137##          21.4 73.7 --   --                  Ex. 64                                                                               ##STR138##     N(n-C.sub.4 H.sub.9).sub.2                                                                         32.4 85.3 --   --                  Ex. 65                                                                               ##STR139##     N(n-C.sub.4 H.sub.9).sub.2                                                                         47.5 64.8 --   --                  Ex. 55                                                                               ##STR140##                                                                                    ##STR141##          --   9.5  34.1 68.7                Ex. 66                                                                               ##STR142##                                                                                    ##STR143##          2.6  19.7 60.4 81.7                Ex. 67                                                                               ##STR144##                                                                                    ##STR145##          9.3  38.3 80.9 --                  Ex. 68                                                                               ##STR146##                                                                                    ##STR147##          9.7  45.3 68.9 --                  Ex. 69                                                                               ##STR148##                                                                                    ##STR149##          36.8 59   76   --                  Ex. 73                                                                               ##STR150##                                                                                    ##STR151##          8.2  66.7 78.3 --                  Ex. 77                                                                               ##STR152##                                                                                    ##STR153##          --   43.2 86   89.8                Ex. 78                                                                               ##STR154##     N(n-C.sub.4 H.sub.9).sub.2                                                                         4.0  59.4 90.3 --                  Ex. 79                                                                               ##STR155##     NHC(CH.sub.3).sub.3  10.3 77.9 94.3 --                  __________________________________________________________________________     ##STR156##                                                                                                                 % of the maximum                                                             contractional effect             Comp. Cy          B'    Am                   10.sup.-5 M                                                                         10.sup.-6 M                                                                         10.sup.-7            __________________________________________________________________________                                                             M                    Ex. 59                                                                               ##STR157## SO.sub.2                                                                             ##STR158##          33.3  81.7  87.5                 Ex. 58                                                                               ##STR159## SO.sub.2                                                                            N(n-C.sub.4 H.sub.9).sub.N                                                                         37    84.7  88.9                 Ex. 62                                                                               ##STR160## SO.sub.2                                                                            NHC(CH.sub.3).sub.3  70.6  87.1  --                   Ex. 60                                                                               ##STR161## SO.sub.2                                                                            N(n-C.sub.4 H.sub.9).sub.2                                                                         20.2  75.5  89.7                 Ex. 61                                                                               ##STR162## SO.sub.2                                                                             ##STR163##          14    70.7  88                   Ex. 56                                                                               ##STR164## S     N(n-C.sub.4 H.sub.9).sub.2                                                                         2.6   58    86.2                 Ex. 57                                                                               ##STR165## S                                                                                    ##STR166##          3.1   59    85                   Ex. 80                                                                               ##STR167## S                                                                                    ##STR168##          3.0   64.2  85.4                 Ex. 81                                                                               ##STR169## SO.sub.2                                                                             ##STR170##          19.2  73.1  86.6                 __________________________________________________________________________    By way of comparison, the following results were obtained with known          compounds:                                                                     ##STR171##                                                                                             % of the maximum contractional effect               Compound     R            10.sup.-6 M 10.sup.-7 M 10.sup.-8 M                 __________________________________________________________________________    A            n-C.sub.4 H.sub.9                                                                          25          60.3        84.3                        B            C.sub.2 H.sub.5                                                                            52.2        84.9        --                          __________________________________________________________________________     ##STR172##                                                                                                                  % of the maximum                                                              contractional effect           Compound   R        R.sub.1                                                                              R.sub.2                                                                              Am           10.sup.-6 M                                                                           10.sup.-7 M            __________________________________________________________________________    Compound C n-C.sub.4 H.sub.9                                                                      H      H      N(n-C.sub.4 H.sub.9).sub.2                                                                 25.0    74.4                   Compound D C.sub.2 H.sub.5                                                                        CH.sub.3                                                                             CH.sub.3                                                                             N(n-C.sub.4 H.sub.9).sub.2                                                                 19.3    64.7                   Compound E C.sub.2 H.sub.5                                                                        H      H      N(n-C.sub.3 H.sub.7).sub.2                                                                 37.9    89.1                   __________________________________________________________________________

Establishing an activity ratio between the compounds of the inventionand the corresponding compounds of the prior art, the following resultswere obtained:

    ______________________________________                                        Compounds        Activity ratio                                               ______________________________________                                        Compound (Ex. 7) 6.0                                                          Compound E                                                                    Compound (Ex. 13)                                                                              2.0                                                          Compound C                                                                    Compound (Ex. 10)                                                                              2.2                                                          Compound D                                                                    ______________________________________                                    

These results show the superiority of the compound of the invention overthe corresponding compounds of the prior art.

II. ANTIADRENERGIC PROPERTIES

The object of this test is to determine the capacity of the compounds ofthe invention for reducing the increase in epinephrine-induced increasein blood-pressure (anti-α affect) and the isoprenaline-inducedacceleration in heart rate (anti-β effect), in dogs previouslyanaesthatized with pentobarbital and atropinized.

For each dog, the dose of epinephrine (between 3 and 10 μg/kg) whichinduced a reproducible increase in the blood-pressure of approximately133×10⁻² Pa and the dose of isoprenaline (1 to 2 μg/kg) which induced areproducible increase in the heart rate of approximately 70 beats/min.were first determined. The dose of epinephrine and of isoprenaline,determined in this manner, were injected alternately every ten minutesand, after two successive reference responses had been obtained, anamount of the test compound was administered intravenously.

Anti-α Effect

The percentage reduction in the hypertension induced by the testcompound compared with the reference hypertension previously obtained(approximately 100 mm Hg) was recorded.

Anti-β Effect

The percentage reduction in the acceleration of the heart rate inducedby the test compound compared with the reference tachycardia measuredpreviously (approximately 70 beats) was recorded.

In both cases, the results of the reduction in blood-pressure or in theheart rate have been expressed as follows:

    ______________________________________                                        +        for a reduction <50%                                                 ++       for a reduction ≧50%                                          +++      for a reduction sub-total (almost complete                                    reduction).                                                          ______________________________________                                    

The following results were recorded:

    ______________________________________                                                  Dose          anti-α                                                                             anti-β                                Compound  (mg/kg)       effect     effect                                     ______________________________________                                        Ex. 7     5             +++        +++                                        Ex. 8     0.5           ++         +                                          Ex. 9     1             ++         ++                                         Ex. 26    0.5           +++        ++                                         Ex. 20    5             +++        +++                                        Ex. 21    5             +++        +++                                        Ex. 2     5             +++        ++                                         Ex. 27    1             +++        ++                                         Ex. 28    0.1           +++        ++                                         Ex. 23    1             +++        +++                                        Ex. 11    1             ++         ++                                         Ex. 12    5             ++         +++                                        Ex. 13    5             ++         ++                                         Ex. 29    5             +++        ++                                         Ex. 14    2.5           +++        +++                                        Ex. 15    2.5           +++        +++                                        Ex. 17    1.3           +++        ++                                         Ex. 30    0.1           +++        +++                                        Ex. 1     0.5           ++         ++                                         Ex. 42    0.1           +++        +++                                        Ex. 43    0.2           +++        +++                                        Ex. 45    0.1           ++         ++                                         Ex. 46    0.1           +++        +++                                        Ex. 47    0.3           ++         +                                          Ex. 49    1             +++        ++                                         Ex. 50    0.1           +++        +++                                        Ex. 51    5.2           +++        ++                                         Ex. 52    5.4           +++        ++                                         Ex. 53    6.1           +++        +                                          Ex. 55     0.13         +++        ++                                         Ex. 59    11.2          ++         ++                                         Ex. 63    10.1          +++        ++                                         Ex. 64    4.9           +          ++                                         Ex. 65     5.89         ++         ++                                         Ex. 66    0.1           +++        +                                          Ex. 67    1.3           +++        +                                          Ex. 68    0.6           +++        ++                                         Ex. 69    1.2           +++        ++                                         Ex. 70     0.12         ++         +                                          Ex. 71     0.13         +++        ++                                         Ex. 72     0.52         ++         +                                          Ex. 73    3             +++        ++                                         Ex. 74    1.2           +++        +                                          Ex. 75    1.3           +++        +                                          Ex. 76     0.13         +++        +                                          Ex. 77    3             +++        ++                                         ______________________________________                                    

By way of comparison, the known compounds showed the followingantiadrenergic effects:

    ______________________________________                                                    Dose         anti-α                                                                            anti-β                                Compound    (mg/kg)      effect    effect                                     ______________________________________                                        Compound A  10           +         0                                          Compound B  10           +++       +                                          Compound C  10           +         0                                          Compound D  10           +         +                                          Compound E  10           +         ++                                          Compound F*                                                                              10           -         0                                          ______________________________________                                         *2-ethyl-1-{4-[3-(di-n-butylamino-propyloxy]benzoyl}-indolizine.         

These results demonstrate that the compounds of the invention show muchgreater α- and β-antiadrenergic activity than those of the compounds ofthe prior art.

III. TOXICITY

The acute toxicity of the compounds of the invention was determinedintravenously in mice according to the method of Litchfield and Wilcoxon(J. Pharm. Exp. Therap. 1946, 96, 99).

The following results were obtained, expressed in the form of the LD₅₀,compared with a benzoylindolizine derivative, in this case2-ethyl-3-{4-[3-(di-n-butylamino) propyloxy]benzoyl}indolizine orbutoprozine.

    ______________________________________                                        Compound      LD.sub.50 (mg/kg)                                               ______________________________________                                        Ex. 6         31                                                              Ex. 11        28                                                              Ex. 7         26                                                              Ex. 18        35                                                              Ex. 19        60                                                              Ex. 13        31                                                              Ex. 9         55                                                              Ex. 28        32                                                              Ex. 30        140                                                             Butoprozine   23                                                              ______________________________________                                    

The results show that the compounds of the invention compare favourablywith butoprozine as regards toxicity.

The therapeutic compositions according to the invention can be presentedin any form suitable for administration in human or veterinary therapy.As regards the administration unit, this can take the form of, forexample, a coated- or uncoated tablet, hard- or soft-gelatin capsule,packaged powder, suspension or syrup for oral administration, asuppository for rectal administration or a solution or suspension forparenteral administration.

The therapeutic compositions of the invention may contain, peradministration unit, for example, from to 500 mg as the weight of activeingredient for oral administration, from 50 to 200 mg of activeingredient for rectal administration and from 50 to 150 mg of activeingredient for parenteral administration.

Depending on the administration route chosen, the therapeuticalveterinary compositions of the invention will be prepared by combiningat least one of the compounds of formula I, or a non-toxic addition saltof this compound, with a suitable excipient, it being possible for thelatter to consist, for example, of at least one ingredient selected fromthe following substances: lactose, starches, talc, magnesium stearate,polyvinylpyrrolidone, alginic acid, colloidal silica, distilled water,benzyl alcohol or sweetening agents.

The following non-limiting examples illustrate the invention:

EXAMPLE 1 Preparation of2-isopropyl-1-{4-[3-(di-n-butylamino)propyloxy]benzenesulphonyl}indolizineoxalate (SR 33513 A) a)2-Isopropyl-1-(4-tosyloxybenzenesulphonyl)indolizine

A mixture of 0.05 mol of 4-tosyloxyphenyl β-picolyl sulphone, 0.15 molof 1-bromo-3-methyl-2-butanone and 0.05 mol of potassium carbonate in100 ml of methyl ethyl ketone was brought to reflux for 22 hours. Afterthis period of time, the reaction medium was brought back to roomtemperature and then filtered. The filtrate was evaporated carefullyunder vacuum so as to drive off the excess bromo ketone. The pastyresidue was taken up in petroleum ether, ground and filtered. The lasttraces of bromo ketone were thereby removed.

The cake obtained was taken up in a mixture of 200 ml of acetone/water(70:30), acidified with a few drops of hydrochloric acid and thenbrought to boiling for a few minutes. After cooling and filtration, awhite solid was isolated which could be recrystallized in anacetone/water mixture.

In this manner, 2-isopropyl-1-(4-tosyloxybenzenesulphonyl) indolizinewas obtained in a 70% yield.

M.p. 180°-183° C.

From suitable starting substances and using the process described above,the following compounds were prepared:

2-Methyl-1-(4-tosyloxybenzenesulphonyl)indolizine

M.P. 169° C. (acetone)

2-Ethyl-1-(4-tosyloxybenzenesulphonyl)indolizine

M.P. 190° C. (acetone)

2-n-Propyl-1-(4-tosyloxybenzenesulphonyl)indolizine

M.P. 189° C. (acetone)

2-Ethyl-1-(3-methyl-4-tosyloxybenzenesulphonyl)indolizine

M.P. 164° C. (methanol/chloroform)

2-n-Butyl-1-(4-tosyloxybenzenesulphonyl)indolizine

M.P. 145° C. (acetone)

2-Phenyl-1-(4-tosyloxybenzenesulphonyl)indolizine

M.P. 168° C. (dichloroethane)

2-Ethyl-1-(3,5-dimethyl-4-tosyloxybenzenesulphonyl)indolizine

M.P. 161 ° C. (acetone)

2-tert-Butyl-1-(4-tosyloxybenzenesulphonyl)indolizine Oily

2-Cyclohexyl-1-(4-tosyloxybenzenesulphonyl)indolizine

M.P. 173°-175° C. (acetone/water)

b) 2-Isopropyl-1-(4-hydroxybenzenesulphonyl)indolizine

0.034 mol of 2-isopropyl-1-(4-tosyloxybenzenesulphonyl)indolizine werepoured into a mixture of 80 ml of water containing 0.34 mol of sodiumhydroxide and 80 ml of ethanol, and the reaction mixture was thenbrought to reflux for 24 hours.

After being cooled, the solution was diluted with 300 ml of water andthen extracted with ethyl ether. After acidification of the aqueousphase, the formation of a precipitate was observed, and this wassuction-filtered and dried.

In this manner, 2-isopropyl-1-(4-hydroxybenzenesulphonyl) indolizine wasobtained in a 90% yield.

M.P. 179°-180° C. (isopropanol/water, 3:1).

From suitable starting substances and using the process described above,the following compounds were prepared:2-Methyl-1-(4-hydroxybenzenesulphonyl)indolizine M.P. 177° C.(methanol/water) 2-Ethyl-1-(4-hydroxybenzenesulphonyl)indolizine M.P.204° C. (ethyl acetate)

2-n-Propyl-1-(4-hydroxybenzenesulphonyl)indolizine

M.P. 225° C. (isopropanol)

2-Ethyl-1-(3-methyl-4-hydroxybenzenesulphonyl)indolizine

M.P. 214° C. (isopropanol)

2-n-Butyl-1-(4-hydroxybenzenesulphonyl)indolizine

M.P. 190° C. (isopropanol)

2-Phenyl-1-(4-hydroxybenzenesulphonyl)indolizine

M.P. 234° C. (methanol)

2-Ethyl-1-(3,5-dimethyl-4-hydroxybenzenesulphonyl)indolizine

M.P. 183° C. (isopropanol)

2-tert-Butyl-1-(4-hydroxybenzenesulphonyl)indolizine

M.P. 169° C. (chloroform/petroleum ether)

2-Cyclohexyl-1-(4-hydroxybenzenesulphonyl)indolizine

M.P. 217° C. (isopropanol/petroleum ether)

c)2-Isopropyl-1-{4-[3-(di-n-butylamino)propyloxy]-benzenesulphonyl}indolizineoxalate.

0.015 mol of 1-chloro-3-(di-n-butylamino)propane and 0.018 mol of afinely ground potassium carbonate were added to 0.012 mol of2-isopropyl-1-(4-hydroxybenzenesulphonyl)indolizine in 100 ml of methylethyl ketone. The mixture was brought to reflux for 24 hours and thenbrought back to room-temperature. The inorganic salts were filtered offand the filtrate was evaporated under the vacuum of a filter pump. Anoil was obtained which was purified by chromatography on a dry aluminacolumn.

The desired compound, in basic form, thus purified could be isolated inthe crystalline state. The oxalate of the product obtained was formed byadding a stoechiometric amount of oxalic acid to a solution of the basedissolved in acetone.

In this manner, 2-isopropyl-1-{4-[3-(di-n-butylamino)propyloxy]benzenesulphonyl}indolizine oxalate was obtained in a 26%yield.

M.P. 133° C. (isopropanol)

2-Cyclohexyl-1-{4-[3-(di-n-butylamino)propyloxy]-benzenesulphonyl}indolizine

M.P. 130°-131° C. (methanol) (SR 33641) (Example 51)

EXAMPLE 2 Preparation of2-ethyl-1-[4-(3-piperidinopropyloxy)benzenesulphonyl]indolizinehydrochloride (SR 33528 A) a)2-Ethyl-1-[4-(3-bromopropyloxy)benzenesulphonyl]indolizine

0.01 mol of 2-ethyl-1-(4-hydroxybenzenesulphonyl)indolizine wasdissolved in 50 ml of methyl ethyl ketone. 0.02 mol of potassiumcarbonate was added and the mixture was brought to reflux for one hour.0.04 mol of 1,3-dibromopropane was then added and refluxing wascontinued for 24 hours. After the reaction, the salts were removed byfiltration and the solution was evaporated to dryness. The residue waspurified by chromatography on a silica column (elution solvent:dichloroethane).

In this manner,2-ethyl-1-[4-(3-bromopropyloxy)benzenesulphonyl]indolizine was obtainedin a 70% yield. M.P. 136° C. (acetone)

From suitable starting substances and using the process described above,the following compounds were obtained:

2-n-Butyl-1-[4-(3-bromopropyloxy)benzenesulphonyl]indolizine

M.P. 119° C. (acetone)

2-Isopropyl-1-[4-(3-bromopropyloxy)benzenseulphonyl]indolizine

M.P. 131 ° C. (acetone)

2-Phenyl-1-[4-(3-bromopropyloxy)benzenesulphonyl]indolizine

M.P. 199° C. (dichloroethane)

2-Ethyl-1-[4-(2-bromoethyloxy)benzenesulphonyl]indolizine Oily

2-Ethyl-1-[4-(4-bromobutyloxy)benzenesulphonyl]indolizine

M.P. 111° C. (cyclohexane)

2-Isopropyl-1-[4-(4-bromobutoxy)benzenesulphonyl]indolizine

M.P. 111° C. (ethyl acetate/petroleum ether)

2-Phenyl-1-[4-(3-bromopropyloxy)-3-methylbenzenesulphonyl]indolizineOily

b) 2-Ethyl-1-[4-(3-piperidinopropyloxy)benzenesulphonyl]indolizinehydrochloride

0.005 mol of 2-ethyl-1-[4-(3-bromopropyloxy)-benzenesulphonyl]indolizinewas dissolved in 25 ml of butanol. 0.01 mol of potassium carbonate and0.01 mol of piperidine were added and the reaction mixture was thenheated on a water bath for 20 hours.

After this period of time, the mixture was evaporated to dryness undervacuum, and an oil was thereby obtained which was taken up in ethylether. An insoluble material composed of salts was removed, and theether solution was evaporated to dryness. The residue was purified bychromatography on a silica column using a chloroform/methanol (8:2)mixture as solvant, and the pure oil obtained was dissolved in a mixtureof acetone and ethyl ether.

The hydrochloride was then formed by adding a solution of hydrochloricacid in ethyl ether.

In this manner, 2-ethyl-1-[4-(3-piperidinopropyloxy)benzenesulphonyl]indolizine hydrochloride was obtained.

Yield: 54% .

M.P. 183° C. (acetone).

EXAMPLE 3 Preparation of2-ethyl-1-{4-[3-(tert-butylamino)propyloxy]benzenasulphonyl}indolizinehydrochloride (SR 33511A)

A mixture of 0.007 mol of 2-ethyl-1-[4-(3-bromopropyloxy)benzenesulphonyl]indolizine and 0.07 mol of tert-butylamine in 50 ml oftoluene was heated on a water bath at 100° C. for 48 hours.

After the reaction, the mixture was carefully evaporated to drynessunder vacuum, and the residue taken up in aqueous sodium hydroxidesolution. The mixture was extracted with dichloromethane and the organicphase was evaporated to dryness. An oily residue was obtained, which waspurified by chromatography on a dry silica column, using adichloromethane/methanol/ammonia mixture as solvent.

The purified desired compound in basic form was taken up in ethylacetate, and the hydrochloride was formed by adding hydrochloric acid,dissolved in ethyl ether, dropwise thereto.

In this manner, 2-ethyl-1-{4-[3-(tert-butylamino)propyloxy]benzenesulphonyl}indolizine hydrochloride was obtained.

Yield: 68% .

M.p. 229°-231° C. ethyl acetate/methanol).

From suitable starting substances and using the processes described inthe above examples, the following compounds were prepared:

2-Methyl-1-{4-[3-(diethylamino)propyloxy]benzenesulphonyl}indolizineoxalate SR 33520A) (Example 4)

M.p. 153° C. (dichloro ethane/methanol)

2-Methyl-1-{4-[3-(di-n-propylamino)propyloxy]benzenesulphonyl}indolizine(SR 33518) (Example 5)

M.p. 107°-108° C. (methanol)

2-Methyl-1-{4-[3-(di-n-butylamino)propyloxy]benzenesulphonyl}indolizineoxalate SR 33133 A Example 6)

M.p. 131° C. (ethyl acetate)

2-Ethyl-1-{4-[3-(di-n-propylamino propyloxy]benzene-sulphonyl}indolizinehydrochloride (SR 33305 A) (Example 7)

M.p. 192° C. (acetone)

2-Ethyl-1-{4-[3-(di-n-butylamino)propyloxy]benzenesulphonyl}indolizinehydrochloride (SR 33306 A) Example 8)

M.p. 153° C. (acetone)

2-Ethyl-1-{4-[3-(di-n-butlamino)propyloxy]-3-methylbenzenesulphonyl}indolizinehydrochloride (SR 33508 A) (Example 9)

M.p. 200°-203° C. (methyl ethyl ketone/methanol)

2-Ethyl-1-{4-[3-(di-n-butylamino)propyloxy]-3,5-dimethylbenzenesulphonyl}indolizinehydrochloride (SR 33538 A) (Example 10)

M.p. 136°-137° C. (ethyl acetate/methanol)

2-n-Propyl-1-{4-[3-(di-n-butylamino)propyloxy]benzenesulphonyl}indolizineoxalate (SR 33220 A) (Example 11)

M.p. 111° C. (isopropanol)

2-n-Butyl-1-{4-[3-(di-n-propylamino)propyloxy]benzenesulphonyl}indolizineoxalate (SR 33507 A) (Example 12)

M.p. 110°-113° C. (isopropanol)

2-n-Butyl-1-{4-[3-(di-n-butylamino)propyloxy]benzenesulphonyl}indolizineoxalate (SR 33504 A) (Example 13)

M.p. 85°-87° C. (ethyl acetate)

2-Isopropyl-1-{4-[3-(dimethylamino)propyloxy]benzenesulphonyl}indolizine(SR 33517) (Example 14)

M.p. 90°-92° C. (diisopropyl ether/diethyl ether)

2-Isopropyl-1-{4-[3-(diethylamino)propyloxy]benzene sulphonyl}indolizine(SR 33516) (Example 15)

M.p. 90°-92° C. (diisopropyl ether)

2-tert-Butyl-1-{4-[3-(di-n-butylamino)propyloxy]benzenesulphonyl}indolizine(SR 33541) (Example 16)

M.p. 90°-92° C. (hexane)

2-Isopropyl-1-{4-[3-(di-n-propylamino)propyloxy]benzenesulphonyl}indolizineoxalate (SR 33512 A) (Example 17)

M.p. 164°-165° C. (methyl ethyl ketone/methanol)

2-Phenyl-1-{4-[3-(di-n-butylamino)propyloxy]benzenesulphonyl}indolizinehydrochloride (SR 33369 A) (Example 18)

M.p. 158° C. (acetone)

2-Phenyl-1-{4-[3-(di-n-butylamino)propyloxy]-3-methylbenzenesulphonyl}indolizinehydrochloride (SR 33486 A) (Example 19)

M.p 194° C. (methanol)

2-Ethyl-1-{4-[3-(N-methyl-N-butylamino)propyloxy]benzenesulphonyl}indolizineoxalate (SR 33533 A) (Example 20)

M.p. 163° C. (acetone)

2-Ethyl-1-{4-[3-(n-butylamino)propyloxy]benzenesulphonyl}indolizineoxalate (SR 33534 A) (Example 21)

M.p. 141° C. (acetone)

2-Ethyl-1-{4-[2-(di-n-butylamino)ethyloxy]benzenesulphonyl}indolizinehydrochloride (SR 33547 A) (Example 22)

M.p. 153° C. (ethyl acetate)

2-Ethyl-1-{4-(di-n-butylamino)butyloxy]benzenesulphonyl}indolizinehemioxalate (SR 33548 A) (Example 23)

M.p. 150° C. (ethyl acetate)

2-Phenyl-1-{4-[3-(tert-butylamino)propyloxy]benzenesulphonyl}indolizinehydrochloride (SR 33370 A) (Example 24)

M.p. 228° C. (acetone)

2-Phenyl-1-{4-[3-(tert-butylamino)propyloxy]-3-methyl-benzenesulphonyl)indolizinehydrochloride SR 33485 A) (Example 25)

M.p. 181° C. (methanol)

2-Ethyl-1-{4-[3-(di-n-pentylamino)propyloxy]benzenesulphonyl}indolizinehydrochloride (SR 33550 A) (Example 26)

M.p. 132°-133° C. (ethyl acetate/methanol)

2-Ethyl-1-{4-[3-(3,4-dimethoxy-S-phenethylamino)propyloxy]benzenesulphonyl}indolizineoxalate (SR 33544 A) (Example 27)

M.p. 179°-181° C. (methanol)

2-Ethyl-1-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]indolizine(SR 33549) Example 28)

M.p. 78°-80° C. (diisopropyl ether)

2-n-Butyl-1-{4-[3-(tert-butylamino)propyloxy]benzenesulphonyl}indolizineoxalate (SR 33503 A) (Example 29)

M.p. 207°-208° C. (methanol)

2-Isopropyl-1-[4-{3-[N-methyl-N-(3,4-dimethoxy-8-phenethyl)amino]propyloxy}benzenesulphonyl]indolizine(SR 33557) (Example 30)

M.p. 82°-83° C. (diisopropyl ether/dichloromethane)

2-Isopropyl-1-{4-[3-(β-phenethylamino)propyloxy]benzenesulphonyl}indolizinehydrochloride (SR 33577 A) (Example 31)

M.p. 209°-210° C. (ethyl acetate/methanol)

2-Isopropyl-1-{4-[3-(benzylamino)propyloxy]benzenesulphonyl}indolizinehydrochloride (SR 33578 A) (Example 32)

M.p. 193°-195° C. (ethyl acetate/methanol)

2-Isopropyl-1-{4-[3-(N-phenylpiperazino)propyloxy]benzenesulphonyl}indolizine(SR 33579) (Example 33)

M.p. 135°-136° C. (methanol/dichloromethane)

2-Isopropyl-1-{4-[3-(2-pyridylethylamino)propyloxy]benzenesulphonyl}indolizinedioxalate (SR 33582 A) (Example 34)

M.p. 154°-156° C. (methanol)

2-Isopropyl-1-4-[3-(4-phenylpiperidino)propyloxy]-benzenesulphonylindolizine(SR 33583) (Example 35)

M.P. 79°-80° C. (methanol)

2-Isopropyl-1-{4-[3-(di-n-octylamino)propyloxy]-benzenesulphonyl}indolizine (SR 33584) (Example 36)

M.P. <50° C. (pasty)

2-Isopropyl-1-{4-[3-(di-n-pentylamino)propyloxy]-benzenesulphonylindolizinehydrochloride (SR 33603 A)(Example 37)

M.P. 138° C. (methyl ethyl ketone/ethyl ether, 2:1)

2-Ethyl-1-{4-[3-(1-imidazolyl)propyloxy]benzenesulphonylindolizine (SR33590) (Example 38)

M.P. 130°-131° C. (ethyl acetate/methanol/ethyl ether)

2-Isopropyl-1-{4-[4-(di-n-butylamino)butyloxy]benzenesulphonyl}indolizine (SR 33606)(Example 39)

M.P. 96° C. (n-hexane)

2-Ethyl-1-{4-[5-(di-n-butylamino)pentyloxy]benzenesulphonyl} indolizine(SR 33607) (Example 40)

M.P. 89°-90° C. (n-hexane)

2-Isopropyl-1-[4-{3-[N-methyl-N-(3,4-dimethoxybenzyl)-amino]propyloxy}benzenesulphonyl]indolizine(SR 33611) (Example 41)

M.P. 96°-100° C. (diisopropyl ether/dichloromethane)

2-Isopropyl-1-[4-{4-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]butyloxy}benzenesulphonyl]indolizine (SR 33620) (Example 42)

M.P. 84°-86° C. (hexane)

2-Isopropyl-1-{4-[3-(3,4-dimethoxybenzyl amino)propyloxy]benzanesulphonyl}indolizine (SR 33621) (Example 43)

M.P. 109°-111° C. (diisopropyl ether/dichloroethane)

2-Isopropyl-1-{4-[3-(3,4-dimethoxyanilino)propyloxy]benzenesulphonyl}indolizine hydrochloride (SR 33624 A) (Example 44)

M.P 200°-203° C. (methylene chloride)

2-Isopropyl-1-[4-{3-[N-n-butyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]indolizine acid oxalate (SR 33629 A)(Example 45)

M.P. 108°-110° C. (ethyl acetate/methanol)

2-Isopropyl-1-[4-{3-[N-methyl-N-(3-methoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]indolizineacid oxalate (SR 33632 A) (Example 46)

M.P. 111°-113° C. (ethyl acetate/methanol)

2-Isopropyl-1-[4-{3-[N-methyl-N-(4-methoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]indolizine acid oxalate (SR 33638 A) Example47)

M.P 140°-144° C. (ethyl acetate/methanol)

2-Isopropyl-1-{4-[3-(4-diphenylmethylpiperazino)propyloxy]benzenesulphonyl}indolizine (SR 33663 A) (Example 48)

M.P. 170° C. (methanol/dichloromethane)

EXAMPLE 49 Preparation of2-isopropyl-1-{4-[3-(di-n-butylamino)-2-hydroxypropyloxy]-benzenesulphonyl}indolizinehydrochloride (SR 33644 A) a)2-Isopropyl-1-[4-(2,3-epoxypropyloxy)benzenesulphonyl] indolizine

While stirring, a mixture of 0.02 mol of2-isopropyl-1-(4-hydroxybenzenesulphonyl)indolizine, 0.02 mol ofpotassium carbonate and 40 ml of epichlorohydrin was heated at 90° C.for 20 hours. After this period of time the epichlorohydrin in excesswas eliminated under vacuum and the residue was taken up in toluene. Thesolution was washed with a dilute sodium hydroxide solution then withwater. The organic phase was evaporated to dryness under vacuum toobtain an oil which was purified on a silica column (eluent:dichloromethane/ethyl acetate 95/5). The desired product slowlycrystallized.

In this manner, 2-isopropyl-1-[4-(2,3-epoxypropyloxy)benzenesulphonyl]indolizine was obtained in a yield of 68%.

M.P. 110°-111° C. (methanol).

b)2-Isopropyl-1-{4-[3-(di-n-butylamino)-2-hydroxypropyloxy]-benzenesulphonyl}indolizinehydrochloride

A solution of 0.0027 mol of2-isopropyl-1-[4-(2,3-epoxypropyloxy)benzenesulphonyl]indolizine and0.015 mol of di-n-butylamine in 10 ml of methanol was refluxed for 1hour. The solution was brought to room-temperature and thedi-n-butylamine in excess was eliminated under vacuum together with thesolvent. The residue obtained was taken up in anhydrous ethyl ether andthe hydrochloride of the desired compound was formed by adding hydrogenchloride in ethyl ether.

In this manner,2-isopropyl-1-{4-[3-(di-n-butylamino)-2-hydroxypropyloxy]-benzenesulphonyl-indolizinehydrochloride was obtained which was recrystallized from anacetone/ethyl ether mixture.

Yield: 68.9% .

M.P. 155°-156° C.

EXAMPLE 50 Preparation of2-isopropyl-1-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]indolizinehydrochloride (SR 33656 A)

To a solution of 0.075 mol of2-isopropyl-1-[4-(2,3-epoxypropyloxy)benzenesulphonyl]indolizinedissolved in 25 ml of methanol, there were added 0.01 mol ofN-methyl-3,4-dimethoxy-β-phenethylamine hydrochloride and 0.011 mol oftriethylamine. The mixture was brought to reflux for 5 hours. Aftercooling the reaction medium was evaporated off to dryness and the oilyresidue was taken up in dichloromethane and slightly alkaline water. Theorganic phase was washed, dried and evaporated off under vacuum. Thecrude compound so obtained was purified by chromatography on a silicacolumn rendered inactive by means of diethylamine (eluent:dichloromethane). The purified product was dissolved in anhydrous ethylether and the hydrochloride of the desired compound was formed by addinghydrogen chloride in ethyl ether. The hydrochloride in questionprecipitated.

In this manner,2-isopropyl-1-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]indolizinehydrochloride was obtained.

M.P. 110° C.

EXAMPLE 52 Preparation of1-{4-[3-(di-n-butylamino)propyloxy]phenylthio}-2-isopropylindolizineoxalate (SR 33650 A) a)1-(3-Methyl-2-oxobutyl)-2-{[(4-hydroxyphenyl)thio]methyl} pyridiniumbromide

A mixture of 0.02 mol of 2-{[(4-hydroxyphenyl)thio]methyl} pyridine and0.03 mol of bromomethylisopropylketone in 160 ml of acetone was heatedto boiling for 24 hours. After this period of time, the reaction mediumwas brought to room-temperature. A precipitate was observed whichincreased by adding pure diethyl ether. This precipitate was filteredout washed with dry diethyl ether and dried under vacuum.

In this manner,1-(3-methyl-2-oxobutyl)-2-{[(4-hydroxyphenyl)thio]methy}pyridiniumbromide was obtained in crude form and used as such.

Yield: 65%

M.P. 175° C.

b) 1-[(4-Hydroxyphenyl)thio]-2-isopropylindolizine

The pyridinium bromide obtained in paragraph a) above was dissolved inwater and sodium bicarbonate in excess was added to this solution. Themixture was heated at 90° C. for 25 minutes and then brought toroom-temperature.

An oil was so obtained which was washed with water by decantation. Thisoil was then dissolved in methanol, the methanolic solution was filteredand evaporated to dryness. The crude product so obtained was purified bychromatography on a silica column (eluent: dichloroethane/hexane 1/1).

In this manner, 1-[(4-hydroxyphenyl)thio]-2-isopropylindolizine wasobtained.

Yield: 90%.

M.P 100° C.

c) 1-{4-[3-(Di-n-butylamino)propyloxy]phenylthio}-2-isopropylindolizineoxalate

Into a solution of 0.01 mol of1-[(4-hydroxyphenyl)thio]-2-isopropylindolizine in 80 ml ofdimethylsulphoxide, there were added 5 g of anhydrous potassiumcarbonate and 0.015 mol of 1-chloro-di-n-butylamino-propane. Thereaction medium was maintained under stirring for 24 hours and thenpoured into 500 ml of water. The solution was extracted with diethylether and the organic phase was washed with water, dried on sodiumsulphate, filtered and evaporated to dryness to obtain the desiredproduct in basic form. This crude compound was dissolved in dry diethylether and a solution of oxalic acid in diethyl ether was added.

In this manner,1-{4-[3-(di-n-butylamino)propyloxy]phenyl-thio}-2-isopropylindolizineoxalate was obtained in a yield of 65%.

M.P. 118° C. (ethanol/diisopropyl ether).

Using the same method as that described above but starting from theappropriate product, the following compound was prepared:

1-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}phenylthio]-2-isopropylindolizine oxalate (SR 33651) (Example 53)

M.P. 110° C.

EXAMPLE 54 Preparation of 4-[3-(di-n-butylamino)propyl]oxyphenyl(2-isopropyl-1-indolizinyl)sulphoxide oxalate (SR 33644)

Into a solution of 0.0017 mol of 1-{4-[3-(di-n-butylamino)propyloxy]phenylthio}-2-isopropylindolizine oxalate, obtained in Example52, in 10 ml of methylene chloride, was added, drop-by-drop at thetemperature of 0° C., a solution of 0.0019 mol of 3-chloroperbenzoicacid in 10 ml of methylene chloride. The reaction medium was allowed toreturn to room-temperature and the reaction was maintained for 15minutes.

The medium was twice washed with an aqueous solution of sodiumbicarbonate then with water. The organic phase was dried on sodiumsulphate, filtered and evaporated to dryness to obtain the desiredproduct in basic form.

This crude compound was dissolved in dry diethyl ether and a solution ofoxalic acid in diethyl ether was added.

In this manner, 4-[3-(di-n-butylamino)propyl]oxyphenyl(2-isopropyl-1-indolizinyl)sulphoxide oxalate was obtained in a yield of20%. M.P. 70° C.

EXAMPLE 55 Preparation of2-isopropyl-3-[4-{3-[N-methyl-N-(3,4-dimethoxy-β- phenethyl)amino]propyloxy}benzenesulphonyl]indolizine oxalate (SR 33700 A) a)1-Ethoxycarbonyl-2-isopropyl-3-(4-methoxybenzenesulphonyl) indolizine

Into 114 ml of 1,2-dichloroethane were dissolved 13.4 g (0.058 mol) of1-carboethoxy-2-isopropylindolizine and 12.7 g (0.061 mol) of4-methoxybenzenesulphonyl chloride. The solution was stirred and cooledto 0° C. while 23 g (0.174 mol) of aluminium chloride were added bysmall fractions.

The addition was terminated after 30 min and the medium was allowed toreturn to room-temperature for 4 hours. After that, the mixture waspoured onto ice and 20 ml of concentrated hydrochloric acid were added.The medium was stirred for 30 min and the organic layer was decanted andwashed with 3 fractions of water. The extract was dried on sodiumsulphate and isolated under vacuum to obtain 24.8 g of a black oil(theory: 23.28 g). This oil was purified on a silica column using firstn-hexane/10%-ethyl acetate and then n-hexane/20%-ethyl acetate aseluents.

In this manner 3.25 g of 1-ethoxycarbonyl2-isopropyl-3-(4-methoxybenzenesulphonyl) indolizine were obtained in aform of a white solid.

Yield: 13.95%.

M.P. 103°-104° C. (hexane/methylene chloride).

b) 1-Carboxy-2-isopropyl-3-(4-hydroxybenzenesulphonyl) indolizine

Into 100 ml of methylene chloride and 25 ml of ethanethiol, weresuspended 6.7 g (0.050 mol) of aluminium chloride. The suspension wasstirred and cooled to 0° C. while 2.5 g of1-ethoxycarbonyl-2-isopropyl-3-(4-methoxybenzenesulphonyl) indolizine inmethylene chloride were added. The addition took about 15 min . Thereaction medium was allowed to return to room-temperature andmaintained, at this temperature, for 45 min. After pouring onto ice, 5ml of concentrated hydrochloric acid were added while stirring and themedium was extracted with 2 fractions of ethyl ether. The etherealextracts were collected and washed with 3 fractions of 30 ml of a10%-aqueous solution of sodium carbonate. The aqueous phase wasacidified and a precipitate was observed.

In this manner 1 g of crude 1-carboxy-2isopropyl-3-(4-hydroxybenzenesulphonyl) indolizine was obtained in theform of a beige solid.

Yield: 44.6%.

c) 2-Isopropyl-3-(4-hydroxybenzenesulphonyl) indolizine

For 2 min, 1 g (2.78×10⁻³ mol) of1-carboxy-2-isopropyl-3-(4-hydroxybenzenesulphonyl) indolizine washeated at 200° C. The black residue so obtained was taken up inmethylene chloride and a slight precipitate was eliminated byfiltration. The filtrate was evaporated to provide 0.8 g of a brown oil(theory: 0.877 g). This oil was purified on a silica column using amethylene chloride/ethyl acetate 95/5 mixture as eluent and 0.6 g of agreen oil was isolated.

In this manner 2-isopropyl-3-(4-hydroxybenzenesulphonyl) indolizine wasobtained.

Yield: 68.4%.

Purity: 97.5%.

d)2-Isopropyl-3-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]indolizineoxalate

At room-temperature, 0.510 g (1.57×10⁻³ mol) of2-isopropyl-3-(4-hydroxybenzenesulphonyl) indolizine, 0.5 g of potassiumcarbonate and 5 ml of dimethylsulphoxide were stirred for 30 min. Tothis mixture 0.524 g (1.45×10⁻³ mol) of1-chloro-3-[N-methyl-N-(3,4-dimethoxy-βphenethyl)amino]propane acidoxalate was added. The stirring was maintained for 16 h atroom-temperature then for 2 h at 50° C. The dimethylsulphoxide waseliminated under vacuum and the residue was taken up in water. Themedium was then twice extracted with ethyl acetate. After that theextracts were twice washed with water and dried on sodium sulphate.After filtration, the filtrate was evaporated under vacuum to obtain0.845 g of an amber-coloured oil. This oil was purified on a silicacolumn using as eluents, ethyl acetate containing 5%, then 10%, then20%-methanol to provide 0.583 g of desired product in free base form(yield: 73%; purity: 99.4%).

The oxalate was formed using 0.530 g of base so obtained and an etherealsolution of oxalic acid. The oxalate was recrystallized from ethylacetate/methanol/ethyl ether.

In this manner 0.473 g of2-isopropyl-3-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethylamino]propyloxy}benzenesulphonyl]indolizineoxalate was obtained in the form of a white solid.

M.P.: 135°-137° C.

EXAMPLE 56 Preparation of 4-{4-[3-(di-n-butylamino propyloxy]phenylthio}pyridine dioxalate (SR 33683 A) a) 4-(4-Hydroxy-phenylthio)pyridine

A mixture of 0.0386 mol of 4-(4-methoxy-phenylthio)pyridinehydrochloride in 100 ml of 47%-hydrobromic acid was heated to boilingfor 6 hours. The hydrobromic acid in excess was then distilled off usinga rotatory evaporator and the residue was taken up in water. Thesolution was twice washed with ethyl ether and neutralized with a sodiumhydroxide aqueous solution. The precipitate which formed was filteredout, washed with water and dried under vacuum at the temperature of 60°C.

In this manner 4-(4-hydroxy-phenylthio) pyridine was obtained in a yieldof 96%.

M.P.: 240° C. (heptane/isopropanol 6/4).

b) 4-{4-[3-(Di-n-butylamino) propyloxy]phenylthio} pyridine dioxalate

A solution of 0.014 mol of 4-(4-hydroxy-phenylthio) pyridine and 3 g offinely crushed anhydrous potassium carbonate in 50 ml ofdimethylsulphoxide was placed under stirring for 30 min. To this medium0.016 mol of 1-chloro 3-(di-n-butylamino) propane was added and thestirring was maintained at room-temperature for 24 hours. The reactionmedium was poured into water and extracted with ethyl ether. The organicphase was washed with water, dried on sodium sulphate and filtered.After the solvent was evaporated off, an oil was provided which waspurified by chromatography on a silica column (eluent: methanol). Therequired compound in free base form so obtained was then transformedinto an oxalate by adding an ethereal solution of oxalic acid.

In this manner 4-{4-[3-(di-n-butylamino) propyloxy]phenylthio} pyridinedioxalate was obtained in a yield of 80%.

M.P.: 153° C. (ethanol)

Using the same procedure as that described above,4-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl-amino]propyloxy}phenylthio]pyridineoxalate (SR 33682A) (Example 57) was obtained.

M.P.: 150° C. (ethanol).

EXAMPLE 58 Preparation of2-{4-[3-(di-n-butylamino)propyloxybenzenesulphonyl}pyridine oxalate (SR33692 A) a) 2-(4-Methoxy-benzenesulphonyl)pyridine

Into 200 ml of dichloromethane was dissolved 0.052 mol of 2-[(4-methoxyphenyl) thio ]pyridine hydrochloride. To this solution, previouslycooled to 0° C., a solution of 0.156 mol of 3-chloro-perbenzoic acid in200 ml of dichloromethane was added drop-by-drop and under stirring. Thereaction medium was-still maintained under stirring for 15 min at 0° C.and then the temperature was brought to 25° C. The mixture was washedwith an aqueous solution of sodium carbonate then with water. Theorganic phase was dried on anhydrous sodium sulphate, filtered anddistilled using a rotatory evaporator. The residue so obtained waspurified by chromatography on a silica column using a1,2-dichloroethane/ethyl acetate 95/5 mixture as eluent.

In this manner 2-(4-methoxy-benzenesulphonyl)pyridine was obtained in ayield of 78%.

M.P.: 112° C. (isopropanol).

Using the same procedure as that described above4-(4-methoxy-benzenesulphonyl)pyridine was prepared.

M.P.: 104° C. (heptane).

b) 2-(4-Hydroxy-benzenesulphonyl)pyridine

A mixture of 0.028 mol of 2-(4-methoxy-benzenesulphonyl)pyridine in 70ml of 47%-hydrobromic acid was heated to reflux for 6 hours. After thisperiod of time, the hydrobromic acid in excess was distilled off. Theresidue so obtained was taken up in water, washed with ethyl ether,treated with active charcoal and filtered. The aqueous solution was thenneutralized with a sodium hydroxide solution and the precipitate whichformed, was filtered out and washed with water. The desired product wasdried under vacuum at 60° C. and recrystallized from aheptane/isopropanol 8/2 mixture.

In this manner 2-(4-hydroxy-benzenesulphonyl)pyridine was obtained in ayield of 88%.

M.P.: 148° C.

Using the same method as that described above,4-(4-hydroxy-benzenesulphonyl)pyridine was prepared.

M.P.: 215° C. (heptane/isopropanol 7/3).

c) 2-{4-[3-(di-n-butylamino) propyloxy]benzenesulphonyl}pyridine oxalate

To a solution of 0.0085 mol of 2-(4-hydroxy-benzenesulphonyl)pyridine in50 ml of dimethylsulphoxide, were added 3 g of finely crushed anhydrouspotassium carbonate. The mixture was then maintained under stirring for30 min and 0.015 mol of 1-chloro-3-(di-n-butylamino)propane was added.Stirring was still maintained for 24 hours and the reaction mixture wasthen poured into water and extracted with ethyl ether. The organic layerwas washed with water, dried on sodium sulphate and filtered. After thefiltrate was evaporated, the desired product so obtained was purified bychromatography on a silica column using methanol as eluent. The purebase so obtained was then transformed into an oxalate by addition ofoxalic acid in ethyl ether.

In this manner 2-{4-[3-(di-n-butylamino propyloxy]benzenesulphonyl}pyridine oxalate was obtained in a yield of 50%.

M.P.: 70° C. (ethyl acetate).

Using the same method as that described above, the following compoundswere prepared:

2-[4-{3-[N-methyl-N-(3,4-dimethoxy- β-phenethyl)amino]propyloxy}benzenesulphonyl]pyridine oxalate (SR 33691 A) (Example 59)

M.P.: 161.9° C. (ethanol)

4-{4-[3-(di-n-butylamino)propyloxy]benzenesulphonyl}pyridine dioxalate(SR 33685 A) (Example 60)

M.P.: 122° C. (ethyl acetate/ethanol 1/1)

4-[4-{3-[N-methyl-N-(3,4dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]pyridine oxalate(SR 33680 A) (Example 61)

M.P.: 160° C. (ethanol)

EXAMPLE 62 Preparation of2-{4-[3-(tertiobutylamino)propyloxy]benzenesulphonyl} pyridine oxalate(SR 33693 A)

To a solution of 0.0042 mol of 2-(4-hydroxy-benzenesulphonyl)pyridine in25 ml of dimethylsulphoxide, was added 1.5 g of finely crushed anhydrouspotassium carbonate. The mixture was stirred for 30 min and 0.0075 molof 1-chloro-3-(N-BOC-tertiobutylamino)propane was added. Stirring wasmaintained for 24 hours and the reaction mixture was then poured intowater. After extraction with ethyl ether the organic phase was washedwith water, dried on sodium sulphate, filtered and evaporated todryness. The oily residue so obtained was stirred at the temperature of185° C. for 20 min and the reaction medium was taken up in water. Themixture was made alkaline with an aqueous solution of sodium hydroxideand extracted with ethyl ether. The ethereal solution was washed withwater, dried on sodium sulphate and filtered. After the solvent waseliminated, a crude product was obtained which was purified bychromatography on a silica column using methanol as eluent. The base sopurified was then transformed into an oxalate by adding an etherealsolution of oxalic acid.

In this manner 2-{4-[3-(tertiobutylamino)propyloxy]benzenesulphonyl}pyridine oxalate was obtained in a yield of 23%.

M.P.: 147° C.

EXAMPLE 63 Preparation of 4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonylbenzene hydrochloride (SR33652 A) a) (4-Hydroxybenzenesulphonyl) benzene

To a solution of 0.05 mol of (4-methoxybenzenesulphonyl)benzene in 150ml of anhydrous benzene, was added 0.02 mol of aluminium chloride andthe reaction medium was maintained for about 15 hours under stirring atroom-temperature. After this period of time, the mixture was poured ontocrushed ice. The organic phase was collected, dried on sodium sulphateand evaporated to dryness.

In this manner (4-hydroxybenzenesulphonyl) benzene was obtained in ayield of 68%.

M.P.: 135° C.

b)4-{3-[N-Methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonylbenzenehydrochloride

To a solution of 0.0147 mol of (4-hydroxybenzenesulphonyl) benzene in 25ml of dimethylsulphoxide, was added 0.0294 mol of potassium carbonateand 0.0147 mol of1-chloro-3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propane. Themixture was maintained under stirring for 24 hours at room-temperatureand 60 ml of water were added. After extraction with ethyl ether, theorganic phase was dried and evaporated to dryness to obtain an oilyproduct. The hydrochloride was formed by adding hydrogen chloride inethyl ether to an ethereal solution of the base so provided.

In this manner, 4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy} benzenesulphonylbenzene hydrochloride wasobtained in a yield of 30%.

M.P. 114° C. (ethanol).

Using the same procedure as that described above, 4-[3-(di-n-butylamino)propyloxy] benzenesulphonylbenzene oxalate was obtained (SR 31810 A).(Example 64)

Yield: 48%.

M.P. 78°-81° C. (isopropanol).

EXAMPLE 65 Preparation of2-n-butyl-1-{4-[3-(di-n-butylamino)propyloxy]benzenesulphonyl}benzimidazoleacid oxalate (SR 33631A) a)2-n-Butyl-1-(4-bromopropoxy-benzenesulphonyl)benzimidazole

A solution of 0.0035 mol of 4-bromopropoxy-benzimidazole, 0.0035 mol of2-n-butyl-benzimidazole and 0.0035 mol of triethylamine in 15 ml ofdioxan was maintained for 7-8 hours under stirring and atroom-temperature. The solvent was eliminated under vacuum to obtain aresidue which was purified by chromatography on a silica column (eluent:dichloromethane/ethyl acetate 9/1).

In this manner 2-n-butyl-1-(4-bromopropoxy-benzenesulphonyl)benzimidazole was obtained and was used as such.

Yield: 50%.

b) 2-n-Butyl-1-{4-[3-(di-n-butylamino) propyloxy]benzenesulphonyl}benzimidazole acid oxalate

To a solution of 0.0017 mol of2-n-butyl-1-(4-bromopropoxy-benzenesulphonyl) benzimidazole in 15 ml ofdimethylsulphoxide was added 0.0034 mol of n-butylamine. The reactionmedium was allowed to stand for 17 hours at room-temperature and thenpoured into 50 ml of water. After extraction, the ethereal phase wasdried and evaporated to dryness. The residue so obtained was purified bychromatography on a silica column (eluent: dichloromethane/ethylacetate) to obtain an oil which was the desired product in the form ofthe free base (yield: 50%). The oxalate of the base so provided wasformed by dissolving the base in question into ethyl ether and adding anethereal solution of oxalic acid.

In this manner 2-n-butyl-1-{4-[3-(di-n-butylamino)propyloxy]benzenesulphonyl} benzimidazole acid oxalate was obtainedafter recrystallization from ethanol.

EXAMPLE 66 Preparation of2-isopropyl-3-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethylamino]propyloxy}benzenesulphonyl benzofuran oxalate (SR 33670 A)

A mixture of 0.0021 mol of 2-isopropyl-3-(4-hydroxybenzenesulphonyl)benzofuran, 0.002 mol of1-chloro-3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino] propane and0.0002 mol of potassium carbonate in 2 ml of N,N-dimethylformamide wasstirred at 100° C. for 1 hour. The medium was then poured into water anddistilled in the presence of ethyl acetate. After that the mixture wasdried on sodium sulphate, filtered and concentrated. The residue wastaken up in ethyl acetate and the solution was purified bychromatography on a silica column using methanol as eluent. The oilyproduct so obtained in free base form was taken up in ethyl acetate andone equivalent of oxalic acid in ethylether was added. The precipitateso formed was filtered out and recrystallized.

In this manner2-isopropyl-3-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]benzofuranoxalate was obtained in a yield of 90%.

M.P.: 151°-158° C. (methanol/ethyl acetate).

Using the same method as that described above, the following compoundswere prepared:

Compounds

2-n-Propyl-3-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]benzofuran oxalate (SR33689 A) (Example 67).

M.P.: 143°-144° C. (methanol/ethyl acetate)

2-n-Propyl-3-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy)benzenesulphonyl]benzothiophene hemioxalate(SR 33688A) (Example 68).

M.P.: 148°-149° C. (methanol/ethyl acetate).

EXAMPLE 69 Preparation of 2-n-butyl-3-[4-{3-[N-methyl-N-(3,4dimethoxy-β-phenethyl) amino]propyloxy}benzenesulphonyl]benzofuranhydrochloride (SR 33646A) a) 2-n-Butyl-3-[4-(3-bromopropyloxy)benzenesulphonyl]benzofuran

To a solution of 0.02 mol of2-n-butyl-3-(4-hydroxy-benzenesulphonyl)-benzofuran in 150 ml ofdimethylsulphoxide, was added 0.06 mol of finely crushed anhydrouspotassium carbonate. The mixture was stirred for 1 hour. After that 0.1mol of 1,3-dibromo-propane was added and the reaction medium was heatedto 50° C. for 6 hours. After the reaction was terminated, the mixturewas filtered and evaporated to dryness under vacuum. The residue soobtained was then taken up in dichloroethane, washed with water, thenwith a dilute solution of sodium hydroxide and finally with water. Theorganic phase was evaporated to dryness under vacuum to obtain aresidual oil which was purified by chromatography on a silica column(eluent: hexane/ethyl acetate 9/1).

In this manner, 2-n-butyl-3-[4-(3-bromopropyloxy)benzenesulphonyl]benzofuran was obtained in a yield of 43%.

b)2-n-Butyl-3-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy)}benzenesulphonyl]benzofuranhydrochloride

A mixture of 0.0086 mol of 2-n-butyl-3-[4-(3-bromopropyloxy)benzenesulphonyl] benzofuran, 4 g of anhydrous potassium carbonate and0.015 mol of N-methyl-3,4-dimethoxy-β-phenethylamine in 50 ml ofdimethylsulphoxide was maintained under stirring for 24 hours. Thereaction medium was poured into water and extracted with ethyl ether.The organic solution was washed with water, dried on sodium sulphate,filtered and evaporated to dryness under vacuum. The oily residue waspurified by chromatography on a silica column using, as eluent, adichlorethane/methanol 9/1 mixture. The hydrochloride of the base soprovided was formed by adding an ethereal solution of hydrogen chloride.

In this manner,2-n-butyl-3-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]benzofuranhydrochloride was obtained in a yield of 38%. M.P.: 60° C. (diisopropylether).

EXAMPLE 70 Preparation of 2-isopropyl-3-{4-[3-(di-n-butylamino)propyloxy]benzenesulphonyl]pyrazolo[1,5-a]pyridine oxalate (SR 33684 A)a) 2-Isopropyl-3-(4-methoxybenzenesulphonyl)pyrazolo[1,6-a]pyridine

A solution of 0.03 mol of 2-isopropyl-pyrazolo[1,5-a]pyridine and 0.03mol of 4-methoxybenzenesulphonyl chloride in 60 ml of dichloroethane wascooled to -24° C. After that 0.068 mol of aluminium chloride was addedin one fraction and the reaction medium was allowed to return toroom-temperature for 3 hours. The mixture was then poured into ice waterand distilled in the presence of ethyl acetate. After drying on sodiumsulphate, the medium was filtered and concentrated. The solid soobtained was then recrystallized from an ethyl acetate/hexane mixture toprovide a produce in the form of a white crystalline solid.

In this manner, 0.018 mol of 2-isopropyl-3-(4-methoxybenzenesulphonyl)pyrazolo[1,5-a]pyridine was obtained.

Yield: 60%.

M.P.: 138°-139° C.

b) 2-Isopropyl-3-(4-hydroxybenzenesulphonyl)pyrazolo[1,5-a]pyridine

A mixture of 0.012 mol of 2-isopropyl-3-(4-methoxybenzenesulphonyl)pyrazolo[1,5-a]pyridine and 0.054 mol of pyridine hydrochloride washeated at 220° C. for 1 hour. Water was then added and the mixture wasdistilled in the presence of ethyl acetate. The medium was dried onsodium sulphate, filtered and concentrated. The solid so obtained wasthen recrystallized from isopropyl ether to provide a white crystallineproduct.

In this manner, 0.012 mol of 2-isopropyl-3-(4-hydroxybenzenesulphonyl)pyrazolo[1,5-a]pyridine was obtained.

Yield: 99%.

M.P.: 146.2° C.

c)2-Isopropyl-3-{4-[3-(di-n-butylamino)propyloxy]benzenesulphonyl}pyrazolo]1,5-a]pyridineoxalate

A mixture of 0.003 mol of 2-isopropyl-3-(4-hydroxybenzenesulphonyl)pyrazolo[1,5-a]pyridine, 0.003 mol of1-chloro-3-(di-n-butylamino)propane and 0.004 mol of potassium carbonatein 6 ml of N,N-dimethylformamide was stirred for 40 min. at 100° C. Thereaction medium was then poured into water and distilled in the presenceof ethyl acetate. After drying on sodium sulphate, the mixture wasfiltered and concentrated. The residue was then purified on a silicacolumn using an ethyl acetate/hexane 3/7 mixture as eluent. The base soobtained, in oily form, was then treated with an ethereal solution ofone equivalent of oxalic acid and the precipitate which formed wasfiltered out and recrystallized from an ethyl ether/isopropanol mixture.

In this manner, 0.0028 mol of 2-isopropyl-3-{4-[3-(di-n-butylamino)propyloxy]benzenesulphonyl}pyrazolo[1,5-a]pyridine oxalate was obtained.

Yield: 92%.

M.P.: 72° C.

Using the same procedure as that described above,2-isopropyl-3-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]pyrazolo(1,5-a]pyridineoxalate was obtained (SR 33679A) (Example 71).

M.P.: 144°-147° C. (isopropanol).

EXAMPLE 72 Preparation of2-isopropyl-3-{4-[3-(tertiobutylamino)propyloxy]benzenesulphonyl}pyrazolo]1,5-a]pyridineoxalate (SR 33686A) a)2-Isopropyl-3-[4-(3-bromopropyloxy)benzenesulphonyl]pyrazolo[1,5-a]pyridin

A mixture of 0.003 mol of 2-isopropyl-3-(4-hydroxybenzenesulphonyl)pyrazolo[1,5-a]pyridine, 0.064 mol of 1,3-dibromopropane and 0.004 molof potassium carbonate in 6 ml of N,N-dimethylformamide was stirred at100° C. for one hour. The medium was then poured into water anddistilled in the presence of ethyl acetate. After drying on sodiumsulphate, the mixture was filtered and concentrated to obtain a residuewhich was purified on a silica column using an ethyl acetate/hexane 1/1mixture.

In this manner, 0.0021 mol of 2-isopropyl-3-[4-(3-bromopropyloxy)benzenesulphonyl]pyrazolo[1,5-a]pyridine was obtained in the form of aviscous oil. Yield: 69%.

b)2-Isopropyl-3-{4-[3-(tertiobutylamino)propyloxy]benzenesulphonyl}pyrazolo[1,5-a]pyridineoxalate

In a flask, a solution of 0.002 mol of2-isopropyl-3-[4-(bromopropyloxy)benzenesulphonyl]pyrazolo[1,5-a]pyridineand 0.008 mol of tertiobutylamine in 4 ml of N,N-dimethylsulphoxide wasstirred at room-temperature for 24 hours. The mixture was poured intowater and then distilled in the presence of ethyl acetate. After dryingon sodium sulphate, the medium was filtered and concentrated to obtain abase in oily form. A solution of this base in an ethyl ether/ethylacetate mixture was then treated with one equivalent of oxalic acid andthe white precipitate so obtained was recrystallized from an ethylether/isopropanol mixture.

In this manner, 0.002 mol of 2-isopropyl-3-{4-[3-(tertiobutylamino)propyloxy]benzenesulphonyl}pyrazolo[1,5-a]pyridine oxalate was obtained.

Yield: 99%.

M.P.: 208° C.

EXAMPLE 73 Preparation of2-isopropyl-3-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]-4,5-dihydro-furan oxalate (SR 33681A)a) 1-(4-Tosyloxybenzenesulphonyl)-3-methyl-butan-2-one

A mixture of 0.1 mol of sodium 4-tosyloxysulphinate and 0.1 mol ofbromomethyl isopropyl ketone in 400 ml of N,N-dimethylformamide wasstirred at 85° C. for 90 min. The mixture was then poured onto ice andfiltered on fritted glass. The pasty residue so obtained wassuccessively washed twice with water, once with 200 ml of ethanol andfinally with ethyl ether. After drying under vacuum for 2 hours thedesired product was provided after recrystallization from ethyl acetate.

In this manner, 0.074 mol of1-(4-tosyloxybenzenesulphonyl)-3-methylbutan-2-one was obtained in theform of a white solid.

Yield: 74%.

M.P.: 160° C.

b) 1-Isobutyryl-1-(4-tosyloxybenzenesulphonyl)cyclopropane

A mixture of 0.05 mol of1-(4-tosyloxybenzenesulphonyl)-3-methylbutan-2-one, (0.05 mol) of1,2-dibromo-ethane and 0.12 mol of potassium carbonate in 100 ml ofN,N-dimethylformamide was stirred at room-temperature for 60 hours. Thereaction mixture was poured into water, acidified with dilutehydrochloric acid and extracted with ethyl acetate. After drying onsodium sulphate, the medium was filtered and concentrated. The residueso obtained was then purified by chromatography on a silica column usingan ethyl acetate/hexane 3/7 mixture as eluent.

In this manner, 0.026 mol of1-isobutyryl-1-(4-tosyloxybenzenesulphonyl)cyclopropane was obtained ina yield of 53%.

M.P.: 106°-107° C.

c) 1-Isobutyryl-1-(4-hydroxybenzenesulphonyl)cyclopropane

Into 85 ml of ethanol heated to 80° C., was dissolved 0.026 mol of1-isobutyryl-1-(4-tosyloxybenzenesulphonyl)cyclopropane. A solution of0.05 mol of sodium hydroxide in 30 ml of water was then added and themedium was maintained at 80° C. for 10 min. The ethanol was eliminatedunder reduced pressure and the residue was taken up in dilutehydrochloric acid and distilled in the presence of ethyl acetate. Afterdrying on sodium sulphate, the medium was filtered and concentrated. Theresidue so obtained was then purified by chromatography on a silicacolumn using an ethyl acetate/hexane 1/1 mixture.

In this manner, 0.016 mol of1-isobutyryl-1-1-(4-hydroxybenzenesulphonyl) cyclopropane was obtainedin the form of a white solid. Yield: 60%.

M.P.: 111°-112° C. (ethyl acetate).

d)1-Isobutyryl-1-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]cyclopropane

A mixture of 0.005 mol of 1-isobutyryl-1-(4-hydroxybenzenesulphonyl)cyclopropane, 0.0048 mol of1-chloro-3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propane and0.005 mol of potassium carbonate in 5 ml of N,N-dimethylformamide washeated at 140° C. for 15 min. The reaction mixture was then poured intowater and distilled in the presence of ethyl acetate. After drying onsodium sulphate, the medium was filtered and concentrated. The residuewas then purified by chromatography on a silica column using an ethylacetate/hexane 1/1 mixture.

In this manner, 0.0033 mol of1-isobutyryl-1-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]cyclopropanewas obtained in oily form.

Yield: 66%.

e)2-Isopropyl-3-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]-4,5-dihydro-furanoxalate

A mixture of 0.002 mol of1-isobutyryl-1-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]cyclopropaneand 0.003 mol of tricaprylylmethyl ammonium chloride was heated at 115°C. for 30 min. The reaction medium was then purified by chromatographyon a silica column using an ethyl acetate/hexane 1/1 mixture to obtain abase in oily form. An ethereal solution of the base so provided was thentreated with one equivalent of oxalic acid in ethyl ether.

In this manner, 0.0013 mol of2-isopropyl-3-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]-4,5-dihydro-furanoxalate was obtained in the form of a white solid.

Yield: 65%.

M.P.: 147.2° C. (methanol).

EXAMPLE 74 Preparation of2-isopropyl-3-{4-[3-(di-n-butylamino)propyloxy]benzenesulphonyl}quinolineoxalate (SR 33695 A) a)2-Isopropyl-3-(4-tosyloxybenzenesulphonyl)quinoline

In a sealed tube a mixture of 0.02 mol of 2-aminobenzaldehyde and 0.02mol of 1-(4-tosyloxybenzenesulphonyl)-3-methyl-butan-2-one was heated at185° C. for 2 hours. The mixture was then taken up in dry ethyl etherand filtered. M.P. of the hydrochloride: about 90° C.

b) 2-Isopropyl-3-(4-hydroxybenzenesulphonyl)quinoline

To a solution of 0.017 mol of 2-isopropyl-3-(4-tosyloxybenzenesulphonyl)quinoline in 250 ml of ethanol, was added a solution of 0.068 mol ofsodium hydroxide in 5 ml of water. The mixture was heated to reflux for2 hours and then the solvent was eliminated. The residue so obtained wastaken up in water and neutralized with acetic acid. The precipitatewhich formed was then filtered out, dried and recrystallized from adichlorethane/heptane 1/1 mixture.

In this manner, 2-isopropyl-3-(4-hydroxybenzenesulphonyl) quinoline wasobtained in a yield of 58%.

M.P.: 185° C.

c) 2Isopropyl-3-{4-[3-(di-n-butylamino)propyloxy]benzenesulphonyl}quinolineoxalate

To a solution of 0.005 mol of2-isopropyl-3-(4-hydroxybenzenesulphonyl)quinoline in 25 ml ofdimethylsulphoxide, was added 0.015 mol of anhydrous potassiumcarbonate. The mixture was stirred for 30 min. and 0.0075 mol of1-chloro-3-(di-n-butylamino)propane was added. The reaction medium wasmaintained under stirring for 24 hours. After this period of time, themixture was poured into water and extracted with ethyl ether. Theorganic phase was washed with water, dried on sodium sulphate, filteredand evaporated to dryness. An oily base was so provided which waspurified by chromatography on a silica column (eluent: isopropanol) andtransformed into an oxalate by adding oxalic acid in ethyl ether.

In this manner2-isopropyl-3-{4-[3-(di-n-butylamino]propyloxy]benzenesulphonyl}quinolineoxalate was obtained in a yield of 55%.

M.P.: 130° C. (ethanol).

Using the same method as that described above,2-isopropyl-3-[4-{3-N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]quinolineoxalate (SR 33694 A) (Example 75).

M.P.: 162° C. (ethanol).

EXAMPLE 76 Preparation of5-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]-6-isopropyl-pyrrolo[1,2-b]pyridazineoxalate (SR 33687A) a) 3-(4-Tosyloxybenzenesulphonyl)methyl-pyridazine

To a solution of 0.13 mol of 3-chloromethyl-pyridazine hydrochloride in400 ml of dimethylsulphoxide was added 0.13 mol of sodium bicarbonate.The mixture was stirred for 30 min. and 0.195 mol of sodium4-tosyloxybenzenesulphonate was introduced. The reaction medium wasmaintained under stirring for 2 hours at room-temperature then for 2hours at 50° C. The mixture was poured into 31of water and theprecipitate so formed was filtered, washed with water and dried undervacuum.

In this manner, 3-(4-tosyloxybenzenesulphonyl)methyl-pyridazine wasobtained in a yield of 82%.

M.P.: 161° C. (ethanol).

b) 5-(4-Tosyloxybenzenesulphonyl)-6-isopropyl-pyrrolo[1,2-b]pyridazine

A mixture of 0.011 mol of 3-(4-tosyloxybenzenesulphonyl)methylpyridazineand 0.011 mol of 1,8-diazabicyclo[5,4,0]undec-7-ene in 40 ml ofhexamethylphosphoramide was heated at 75° C. for 30 min. After that 4 gof bromomethyl isopropyl ketone were added while maintaining the sametemperature for 6 hours. The mixture was poured into 200 ml of water andextracted with dichloroethane. The organic solution was washed withwater, dried on sodium sulphate and filtered. The solvent was eliminatedunder vacuum to provide an oily residue which was purified bychromatography on a silica column (eluent: dichloroethane).

In this manner, 5-(4-tosyloxybenzenesulphonyl)-6-isopropyl-pyrrolo[1,2-b]pyridazine was obtained in crystalline form.

Yield: 7%.

M.P.: 149° C. (isopropanol).

c) 5-(4-Hydroxybenzenesulphonyl)-6-isopropyl-pyrrolo[1,2-b]pyridazine

A solution of 0.0034 mol of5-(4-tosyloxybenzenesulphonyl)-6-isopropylpyrrolo[1,2-b]pyridazine in 75ml of ethanol was heated to boiling and a solution of 0.0034 mol ofsodium hydroxide in 3 ml of water was added. Boiling was maintained for6 hours. The solvent was eliminated and the residue was taken up inwater and neutralized with acetic acid. The precipitate so formed wastaken up in dichloroethane and the solution was washed with water, driedon sodium sulphate and filtered. The solvent was finally evaporated off.

In this manner, 5-(4-hydroxybenzenesulphonyl)-6-isopropyl-pyrrolo[1,2-b]pyridazine was isolated in a yield of 75%.

c)5-[4-{3-[N-Methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]-6-isopropyl-pyrrolo[1,2-b]pyridazineoxalate

A mixture of 0.0022 mol of5-(4-hydroxybenzenesulphonyl)-6-isopropylpyrrolo[1,2-b]pyridazine and 15g of anhydrous potassium carbonate in 25 ml of dimethylsulphoxide wasstirred for 30 min. After that, 0.0027 mol of1-chloro-3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propane oxalatewas added and stirring was maintained at room-temperature for 18 hours.The reaction medium was then heated at 50° C. for 5 hours, poured intowater and extracted with ethyl ether. The ethereal phase was washed withwater, dried on sodium sulphate and filtered. After evaporating thesolvent, an oily residue was obtained which was purified bychromatography and a silica column using methanol as eluent. The oxalatewas formed by adding oxalic acid in ethyl ether to an ethereal solutionof the base so provided.

In this manner,5-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]-6-isopropyl-pyrrolo[1,2-b]pyridazineoxalate was obtained in a yield of 57% M.P.: 88° C. (ethylacetate/isopropanol).

EXAMPLE 77 Preparation of2-isopropyl-3-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]furan oxalate (SR 33697 A) a)2-Isopropyl-3-(4-tosyloxybenzenesulphonyl)-4,5-dihydro-furan

A mixture of 0.008 mol of 1-isobutyryl-1-(4-tosyloxybenzenesulphonyl)cyclopropane and 0.022 mol of tricaprylylmethyl ammonium chloride washeated at 130° C. for 30 min. The reaction mixture was thenchromatographed on a silica column using an ethyl acetate/hexane 25/75mixture as eluent.

In this manner, 0.0145 mol of2-isopropyl-3-(4-tosyloxybenzenesulphonyl)-4,5-dihydro-furan wasobtained in the form of a white solid.

Yield: 66 %.

M.P.: 103° C. (ethyl acetate/hexane).

b) 2-Isopropyl-3-(4-tosyloxybenzenesulphonyl) furan

A mixture of 0.035 mol of2-isopropyl-3-(4-tosyloxybenzenesulphonyl)-4,5-dihydro-furan, 1 mol ofmanganese dioxide and 3 Å A-molecular screen in powder (previously driedat 140° C. under 0.01 mm Hg for 5 h) in 400 ml of dry ethyl ether wasstirred for 66 hours at room-temperature. The mixture was then filteredand the solid was rinsed with dichloromethane. After concentration themedium was chromatographed on a silica column using an ethylacetate/hexane 2/8 mixture.

In this manner, 0.009 mol of2-isopropyl-3-(4-tosyloxybenzenesulphonyl)furan was obtained in a yieldof 25%.

M.P.: 94° C. (ethyl acetate/hexane).

c) 2-Isopropyl-3-(4-hydroxybenzenesulphonyl)furan

To a solution of 0.008 mol of2-isopropyl-3-(4-tosyloxybenzenesulphonyl)furan in 1.8 ml of ethanolwere added 18 ml of 1N-sodium hydroxide. The milky solution was stirredunder reflux to complete dissolution (2 minutes) and the reaction mediumwas cooled and neutralized with dilute hydrochloric acid. After that,the mixture was distilled in the presence of ethyl acetate. The organicphase was dried on sodium sulphate, filtered and concentrated. Theresidue so obtained was then purified on a silica column and elutedusing an ethyl acetate/hexane 4/6 mixture.

In this manner, 0.0073 mol of 2-isopropyl-3-(4-hydroxybenzenesulphonyl)furan was obtained in a yield of 91%.

M.P.: 131° C. (ethyl acetate/hexane).

d)2-Isopropyl-3-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]furanoxalate

A mixture of 0.003 mol of 2-isopropyl-3-(4-hydroxybenzenesulphonyl)furan, 0.003 mol of1-chloro-3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propane and3.23×10⁻³ mols of crushed potassium carbonate in 3 ml ofN,N-dimethylformamide was heated at 100° C. for 30 minutes. The mixturewas then poured into water and distilled in the presence of ethylacetate. After drying on sodium sulphate, the medium was filtered andconcentrated. The residue so obtained was then purified bychromatography on a silica column using methanol as eluent. After that,the base so provided was transformed into oxalate by adding oxalic acidin ethyl ether.

In this manner, 0.00288 mol of2-isopropyl-3-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy)}benzenesulphonyl]furanoxalate was obtained.

Yield: 96%.

M.P.: 102° C. (chloroform/ethyl acetate).

Using the same method as described above,2-isopropyl-3-{4-[3-(di-n-butylamino)propyloxy]benzenesulphonyl}furanoxalate (SR 33701 A) (Example 78) was obtained in a yield of 92%.

M.P.: 98° C. (ethanol/ethyl ether).

EXAMPLE 79 Preparation of2-isopropyl-3-{4-[3-(tert-butylamino)propyloxy]benzenesulphonyl}furanoxalate (SR 33701 A) a)2-Isopropyl-3-[4-(3-bromopropyloxy)benzenesulphonyl]furan

A mixture of 0.003 mol of 2-isopropyl-3-(4-hydroxylbenzenesulphonyl)furan, 0.06 mol of 1,3-dibromopropane and 0.005 mol of crushed potassiumcarbonate in 8 ml of N,N-dimethylformamide was heated at 100° C. for 1hour. The mixture was poured into water and distilled in the presence ofethyl acetate. After drying on sodium sulphate, the medium was filteredand concentrated. The residue so obtained was then purified bychromatography on a silica column using an ethyl acetate/hexane 2/8mixture.

In this manner, 0.00282 mol of 2-isopropyl-3-[4-(3-bromopropyloxy)benzenesulphonyl]furan was obtained in oily form.

Yield: 94%.

b) 2-Isopropyl-3-{4-[3-(tert-butylamino)propyloxy]benzenesulphonyl}furanoxalate

A mixture of 0.00282 mol of2-isopropyl-3-[4-(3-bromopropyloxy)benzenesulphonyl]furan and 0.013 molof tert-butylamine in 7 ml of dimethylsulphoxide was stirred atroom-temperature for 24 hours. After that, the mixture was poured intowater, distilled in the presence of ethyl acetate, dried on sodiumsulphate, filtered and concentrated. The residue so obtained waspurified on a silica column using a methanol/ethyl acetate 2/8 mixtureas eluent. The oily base so provided was then treated with an etherealsolution of oxalic acid and the precipitate was recrystallized fromethanol.

In this manner, 0.0023 mol of 2-isopropyl-3-{4-[3-(tert-butylamino)propyloxy]benzenesulphonyl}furan oxalate was obtained in a yield of 82%.

M.P.: 143.6° C.

EXAMPLE 80 Preparation of4-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}phenylthio]cinnolineoxalate (SR 33699A) a) 4-(4-Methoxyphenylthio)cinnoline

To a solution of sodium methylate prepared from 0.7 g (0.03 at g.) ofsodium in 25 ml of methanol, there were added 4.2 g (0.03 mol) of4-methoxyphenylthiol. The methanol in excess was eliminated using arotatory evaporator and the sodium salt so obtained was dried under highvacuum and then dissolved into 100 ml of N,N-dimethylformamide. Afterthat, 4.38 g (0.03 mol) of 4-chlorocinnoline were added. The medium wasstirred at room-temperature for 24 hours and then poured into water.After filtration, the product was washed on the filter with water andthen dried under vacuum at the temperature of 60° C.

In this manner 6.4 g of 4-(4-methoxyphenylthio)cinnoline were obtainedin a yield of 80%.

M.P.: 163° C. (7/3 isopropanol/heptane)

Using the same procedure as that described above but from3-bromocinnoline there was obtained 3-(4-methoxyphenylthio)cinnoline

Yield: 74.6%

M.P.: 108° C. (isopropanol).

b) 4-(4-Hydroxyphenylthio)cinnoline

To a solution of 3.6 g (0.0134 mol) of 4-(4-methoxyphenylthio)cinnoline,there were added 30 ml of 47%-hydrobromic acid. The mixture was stirredand heated at 125° C. for 4 hours. The hydrobromic acid in excess wasthen eliminated with a rotatory evaporator and the residue obtained wastaken up with water. The solution was neutralized with sodiumbicarbonate and filtered. The product so isolated was washed on thefilter with water and dried under vacuum at the temperature of 60° C.

In this manner, 2.9 g of 4-(4-hydroxyphenylthio)cinnoline were obtainedafter recrystallization from a 7/3 isopropanol/heptane mixture.

Yield: 85%

M.P.: 238° C.

Using the same procedure described above but from3-(4-methoxyphenylthio)cinnoline, there was obtained3-(4-hydroxyphenylthio)cinnoline in a yield of 90%.

c)4-4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}phenylthio]cinnolineoxalate

A mixture of 2.5 g (0.01 mol) of 4-(4-hydroxyphenylthio)cinnoline and 7g of crushed anhydrous potassium carbonate in 50 ml ofdimethylsulphoxide was stirred for 30 min. After that 4.4 g (0.012 mol)of 1-chloro-3-[N-methyl-N -(3,4-dimethoxy-β-phenethyl)amino]propaneoxalate were added while stirring was maintained for 24 hours atroom-temperature. The medium was poured into water and extracted withethyl ether. The ethereal solution was washed with water, dried onanhydrous sodium sulphate and filtered. The ethyl ether was eliminatedwith a rotatory evaporator to obtain 5.3 g of an oil which was purifiedby chromatography on a silica column using methanol as eluent. The baseso provided (4.7 g) was then transformed into an oxalate in ethyl ethermedium and the salt was recrystallized from ethanol.

In this manner 4.1 g of 4-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}phenylthio]cinnoline oxalate were obtained.

Yield: 70.8%

M.P.: 138 and 160° C.

Using the same procedure as that described above but from3-(4-hydroxyphenylthio)cinnoline there was prepared3-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}phenylthio]cinnolineoxalate (Example 82) (SR 33704 A)

Yield: 67.6%

M.P.: 166° C.

EXAMPLE 81 Preparation of3-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]cinnolineoxalate (SR 33703A) a) 3-(4-Hydroxybenzenesulphonyl)cinnoline

A mixture of 2.1 g (0.01 mol) of 3-bromocinnoline, 6.6 g (0.02 mol) ofsodium 4-tosyloxybenzenesulphinate and 50 ml of dimethylsulphoxide wasstirred and heated at 120° C. for 24 hours. The mixture was poured intowater and extracted with dichloroethane. The dichloroethane solution waswashed with water, dried on anhydrous sodium sulphate and filtered. Thesolvent was then evaporated with a rotatory evaporator to provide 2.5 gof an oily residue. The desired product was then isolated bychromatography on a silica column using dichlorethane/methanol 98/2.

In this manner, 0.45 g of 3-(4-hydroxybenzenesulphonyl)cinnoline wasobtained.

Yield: 10.2%

b) 3-[4-{3-[N-Methyl-N-(34-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]cinnolineoxalate

A mixture of 0.2 g (0.0007 mol) of3-(4-hydroxybenzenesulphonyl)cinnoline and 0.4 g of potassium carbonatein 10 ml of dimethylsulphoxide was stirred for 30 min. After that, 0.3 g(0.0008 mol) of1-chloro-3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propane oxalatewas added and the stirring was maintained for 24 hours atroom-temperature. The medium was poured into water and extracted withethyl ether. The ethereal solution was washed with water, dried onanhydrous sodium sulphate and filtered. The ethyl ether was theneliminated using a rotatory evaporator and the residue was purified bychromatography on a silica column using methanol as solvent to provide0.100 g (30%) of a base. This base was then transformed into an oxalatein ethyl ether by adding an ethereal solution of oxalic acid and thesalt so formed was recrystallized from ethanol.

In this manner, 0.100 g of3-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]cinnoline oxalate was obtained.

M.P.: 158° C.

EXAMPLE 83 Preparation of2-isopropyl-1-[4-{3-[N-methyl-N-oxide-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]indolizineacid oxalate.

A solution of 2.75 g (0.005 mol) of2-isopropyl-1-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]indolizinein 40 ml of dichloromethane was cooled to -10° C. Under stirring, 1 g(0.005 mol) of 3-chloro-perbenzoic acid in 40 ml of dichloromethane wasadded to the reaction medium which was then allowed to return toroom-temperature. The mixture was washed with a sodium carbonatesolution and then with water. After drying on sodium sulphate andfiltering, the solvent was evaporated off using a rotatory evaporator.The residue so obtained (3.1 g) was then purified by chromatography on asilica column using methanol as solvent to obtain the required N-oxidederivative in free base form. The oxalate was then formed by adding anethereal solution of oxalic acid to a solution, of the base so provided,in tetrahydrofuran/ethyl ether.

In this manner,2-isopropyl-1-[4-{3-[N-methyl-N-oxide-N-(3,4-dimethoxy-β-phenethyl)aminopropyloxy}benzenesulphonyl]indolizineacid oxalate was obtained.

The N.M.R. spectrum was found to be correct.

EXAMPLE 84 Preparation of1-benzyl-2-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]imidazole. a) N-Benzylimidazole

To a solution of 24 g (1 mol) of sodium hydride in 500 ml ofN,N-dimethylformamide, there was added, drop-by-drop, a solution of 68 g(1 mol) of imidazole in 150 ml of N,N-dimethylformamide. The medium wasstirred for 2 hours and then 126.6 g (1 mol) of benzyl chloride wereadded. The solvent was eliminated and the residue was taken up withethyl acetate and washed with water. The organic phase was dried andconcentrated to provide an oil which crystallized when cold.

In this manner, N-benzylimidazole was obtained in a yield of 70%.

b) 1-Benzyl-2-(4-methoxybenzenesulphonyl)imidazole

To a solution of 44 g (0.28 mol) of 1-benzylimidazole in 200 ml ofacetonitrile, there were added, drop-by-drop, 57.5 g (0.28 mol) of4-methoxybenzenesulphonyl chloride dissolved into 50 ml of acetonitrile.After one hour, 41.5 ml (0.31 mol) of triethylamine were added and themedium was maintained under stirring for 12 hours. The precipitate wasisolated and the solution was purified by high pressure liquidchromatography using dichloromethane as eluent.

In this manner, 1-benzyl-2-(4-methoxybenzenesulphonyl)imidazole wasobtained in a yield of 5%.

c) 1-Benzyl-2-(4-hydroxybenzenesulphonyl)imidazole

A mixture of 2.6 g (8×10⁻³ mol) of1-benzyl-2-(4-methoxybenzenesulphonyl)imidazole in 10 ml of iodhydricacid was heated for 5 at 170° C. The reaction medium was then pouredinto ice water and extracted with ethyl acetate. The organic phase wasdried and concentrated and the residue obtained was purified by highpressure liquid chromatography using dichloromethane as eluent.

In this manner, 1-benzyl-2-(4-hydroxybenzenesulphonyl)imidazole wasobtained in a yield of 20%.

d)1-Benzyl-2-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl}benzenesulphonyl]imidazole

A mixture of 0.5 g (1.6×10⁻³ mol) of1-benzyl-2-(4-hydroxybenzenesulphonyl)imidazole, 0.86 g (2.4×10⁻³ mol)of 1-chloro-3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propaneoxalate and 1.1 g (7.9×10⁻³ mol) of potassium carbonate in 6 ml ofdimethylsulphoxide was maintained at 35° C. for 3 days. The reactionmedium was then poured into ice water and the oil so obtained waspurified by high pressure liquid chromatography using ethyl acetate aseluent. Yield: 78%.

EXAMPLE 85 Preparation of1-isopropyl-2-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]benzimidazole oxalate a)1-Isopropyl-2-(4-benzyloxybenzenesulphonyl)benzimidazole

To a solution of 7.08×10⁻⁴ mol of 4-benzyloxybenzenesulphonyl chloridein 10 ml of acetonitrile cooled to 0° C., there was added 7.08×10⁻⁴ molof 1-isopropylbenzimidazole prepared in N,N-dimethylformamide frombenzimidazole and isopropyl bromide in the presence of sodium hydride.After that one equivalent of triethylamine was added. The medium wasstirred at room-temperature for 12 hours and the acetonitrile was thenevaporated off. The residue so obtained was then taken up with water andextracted several times with dichloromethane. The organic extracts werecollected, dried and evaporated. The residue so provided was purified bychromatography on a silica column using a dichloromethane/ethyl acetate99/1 mixture as eluent.

In this manner, 1-isopropyl-2-(4-benzyloxybenzenesulphonyl)benzimidazolewas obtained in a yield of 52%.

M.P.: 94°-96° C.

b) 1-Isopropyl-2-(4-hydroxybenzenesulphonyl)benzimidazole

To 20 ml of ethanol, there were added 2.95×10⁻⁴ mol of1-isopropyl-2-(4-benzyloxybenzenesulphonyl)benzimidazole and 0.015 g of10%-palladium charcoal and the mixture so obtained was maintained underhydrogen atmosphere. When the required quantity of hydrogen was absorbednamely after about 2 hours, the catalyst was filtered out and washedwith ethanol. The alcoholic extracts were collected and evaporated undervacuum.

In this manner 1-isopropyl-2-(4-hydroxybenzenesulphonyl)benzimidazolewas obtained in the form of a white crystalline product.

Yield: 64%.

M.P.: 198° C.

c)1-Isopropyl-2-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]benzimidazoleoxalate.

To a mixture of 1.42×10⁻⁴ mol of1-isopropyl-2-(4-hydroxybenzenesulphonyl)benzimidazole and 5 equivalentsof potassium carbonate in 5 ml of dimethylsulphoxide, there was added1.5 equivalent of1-chloro-3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propane oxalate.The medium was stirred for about 15 hours at 35° C. and the residue waspoured on ice and extracted with ethyl acetate. The organic phase wasthen dried and evaporated and the base so provided was purified bychromatography on a silica column using an ethyl acetate/ methanol 95/5mixture. The oxalate was then formed using an ethereal solution ofoxalic acid.

In this manner,1-isopropyl-2-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxyl}benzenesulphonyl]benzimidazoleoxalate was obtained.

EXAMPLE 86 Preparation of2-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]pyrimidineoxalate a) 2-(4-Methoxybenzenesulphonyl)pyrimidine

To 8.7×10⁻² mol of 50%-sodium hydride in 20 ml of N,N-dimethylformamide,there were added 12.3 g (8.7×10⁻² mol) of 4-methoxyphenylthiol. Afterthe gaseous evolution was terminated namely after about 2 hours, 10 g(8.7×10⁻² mol) of 2-chloropyrimidine in 100 ml of N,N-dimethylformamidewere added. The medium was stirred at room-temperature for 3 hours andthe slight precipitate was filtered out. After evaporation of thesolvent, the oily residue was taken up in 100 ml of water and themixture was stirred. The product which crystallized was then filteredout and washed with water.

In this manner 2-(4methoxybenzenesulphonyl)pyrimidine was obtained in ayield of 89%.

M.P.: 72° C.

b) 2-(4-Hydroxybenzenesulphonyl)pyrimidine

A mixture of 4.6×10⁻³ mol of 2-(4-methoxybenzenesulphonyl)pyrimidine and10 ml of 47%-hydrobromic acid was heated for 1 hour at 90° C. Thereaction medium was neutralized to a pH of 7 with an ammonia solutionand the pasty residue was extracted with dichloromethane. The organicphase was then dried and evaporated and the residue so provided waspurified by chromatography on a silica column using dichloromethane aseluent.

In this manner, 2-(4-hydroxybenzenesulphonyl)pyrimidine was obtained.

c)2-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]pyrimidineoxalate

To a mixture of 1.6×10⁻³ mol of 2-(4-hydroxybenzenesulphonyl)pyrimidine, 2.4×10⁻³ mol of1-chloro-3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propane oxalateand 1.1 g of potassium carbonate was maintained at 35° C. for severalhours and the residue was poured on ice and extracted with ethylacetate. The organic phase was then dried and evaporated and the base soprovided was purified by chromatography on a silica column. The oxalatewas then formed using an ethereal solution of oxalic acid.

In this manner2-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]pyrimidineoxalate was obtained.

EXAMPLE 87 Preparation of2-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyl-oxy}benzenesulphonyl]indeneoxalate. a) 3-Chloro-2-(4-tosyloxybenzenesulphonyl)indane

Under nitrogen atmosphere, a mixture of 0.05 mol of indene, 0.05 mol ofsulphonyl chloride, 0.0005 mol of cupric chloride and 0.0005 mol oftriethylamine hydrochloride in 3 ml of acetonitrile was heated at 115°C. for 2 hours. The medium was then poured into methanol and theprecipitate which formed was filtered and recrystallized from an ethylacetate/chloroform mixture.

In this manner, 0.042 mol of 3-chloro-2-(4-tosyloxybenzenesulphonyl)indane was obtained in a yield of 84%.

M.P.: 176° C.

b) 2-(4-Tosyloxybenzenesulphonyl)indene

A mixture of 0.025 mol of 3-chloro-2-(4-tosyloxybenzenesulphonyl) indaneand 0.04 mol of triethylamine in 125 ml of chloroform was stirred for 4hours at room-temperature. The medium was poured into water anddistilled in the presence of chloroform. The organic phase was dried onsodium sulphate, filtered and concentrated. The green solid so obtainedwas recrystallized first from tetrahydrofuran and then from ethylacetate.

In this manner, 0.024 mol of 2-(4-tosyloxybenzenesulphonyl)indene wasobtained in the form of a white solid.

Yield: 82%.

M.P.: 174° C.

c) 2-(4-Hydroxybenzenesulphonyl)indene

A suspension of 0.01 mol of 2-(4-tosyloxybenzenesulphonyl)indene in 100ml of 2N-sodium hydroxide and 160 ml of ethanol was heated to 80° C.After complete dissolution, the reaction medium ws poured into water,acidified with dilute hydrochloric acid and distilled in the presence ofdichloromethane. The residue was stirred in the presence of animalcharcoal and sodium sulphate and then filtered and concentrated.

In this manner 0.005 mol of 2-(4-hydroxybenzenesulphonyl)indene wasobtained in a yield of 52%.

M.P.: 209°-210° C. (ethyl acetate/hexane).

d)-2-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]indeneoxalate.

A mixture of 0.005 mol of 2-(4-hydroxybenzenesulphonyl)indene and 3.5 gof crushed potassium carbonate in 10 ml of dimethylsulphoxide wasstirred for 30 min. After that, 0.006 mol of1-chloro-3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propane oxalatewas added while stirring was maintained for 24 hours atroom-temperature. The medium was poured into water and extracted withethyl ether. The ethereal solution was washed with water, dried onanhydrous sodium sulphate and filtered. The ethyl ether was eliminatedwith a rotatory evaporator and the residue so obtained was purified bychromatography on a silica column. The base so provided was thentransformed into an oxalate by adding oxalic acid in ethyl ether.

In this manner2-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]indeneoxalate was obtained.

M.P.: 176° C. (ethanol/isopropanol).

EXAMPLE 88

According to known pharmaceutical techniques, a capsule containing thefollowing ingredients was prepared:

    ______________________________________                                        Ingredient           mg                                                       ______________________________________                                        Compound of the invention                                                                          100.0                                                    Starches              99.5                                                    Colloidal silica      0.5                                                                          200.0                                                    ______________________________________                                    

We claim:
 1. An aminoalkoxyphenyl compound of formula: ##STR173## inwhich: B is selected from --S--, --SO-- and --SO₂ --;R₁ and R₂, whichare identical or different, are selected from hydrogen, methyl, ethyland halogen; A is selected from a straight- or branched-alkylene radicalhaving from 2 to 5 carbon atoms, a 2-hydroxypropylene radical, and a2-(lower alkoxy)propylene radical; R₃ is selected from alkyl having from1 to 8 carbon atoms and a radical of formula Alk-R₅, in which Alk isselected from a single bond and a linear- or branched-alkylene radicalhaving from 1 to 5 carbon atoms, and R₅ is selected from pyridyl,phenyl, 2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl and phenylsubstituted with one or more substituents, which may be identical ordifferent, selected from halogen atoms, lower alkyl groups having from 1to 4 carbon atoms, and lower alkoxy groups having from 1 to 4 carbonatoms; R₄ is selected from hydrogen and alkyl having from 1 to 8 carbonatoms; R is selected from hydrogen, C₁₋₈ alkyl, C₃₋₆ cycloalkyl, benzyland phenyl optionally substituted with one or more substituents, whichmay be identical or different, selected from halogen, lower C₁₋₄ alkyl,lower C₁₋₄ alkoxy and nitro; as well as the N-oxide derivative thereofand a pharmaceutically acceptable salt thereof.
 2. An aminoalkoxyphenylcompound of formula: ##STR174## in which: R is selected from hydrogen,C₁₋₈ alkyl, C₃₋₆ cycloalkyl, benzyl and phenyl optionally substitutedwith one or more substituents, which may be identical or different,selected from halogen, lower C₁₋₄ -alkyl, lower C₁₋₄ alkoxy and nitro;R₁and R₂, which are identical or different, are selected from hydrogen,methyl, ethyl and halogen; A is selected from a straight- orbranched-alkylene radical having from 2 to 5 carbon atoms, a2-hydroxypropylene radical, and a 2-(lower alkoxy)propylene radical; Alkis selected from a single bond and a linear- or a branched-alkyleneradical having from 1 to 5 carbon atoms; R₅ is selected from pyridyl,phenyl, 2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl and phenylsubstituted with one or more substituents which may be identical ordifferent, selected from halogen, C₁₋₈ alkyl and C₁₋₈ alkoxy; R₄ isselected from hydrogen and C₁₋₈ alkyl, as well as the N-oxide derivativethereof and the pharmaceutically acceptable salt thereof.
 3. Anaminoalkoxyphenyl compound according to claim 2 in which Alk-R₅represents a [N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxygroup.
 4. An aminoalkoxyphenyl compound according to claim 2 in which Rrepresents an isopropyl or cyclopropyl group.
 5. An aminoalkoxyphenylcompound according to claim 2 which is2-isopropyl-3-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propyloxy}benzenesulphonyl]pyrazolo[1,5-a]pyridineand its N-oxide and pharmaceutically acceptable salts;2-isopropyl-3-{4-[3-(di-n-butylamino)propyloxy]benzenesulphonyl}pyrazolo[1,5-a]pyridineand its N-oxide and pharmaceutically acceptable salts;2-isopropyl-3-{4-[3-(tertiobutylamino)propyloxy]benzenesulphonyl}pyrazolo[1,5-a]pyridineand its N-oxide and pharmaceutically acceptable salts.
 6. Anaminoalkoxyphenyl compound according to claim 2 wherein thepharmaceutically acceptable salt is the oxalate or hydrochloride.
 7. Anaminoalkoxyphenyl compound of formula: ##STR175## in which: R₁ and R₂,which are identical or different, are selected from hydrogen, methyl,ethyl and halogen;A is selected from a straight- or branched-alkyleneradical having from 2 to 5 carbon atoms, a 2-hydroxypropylene radical,and a 2-(lower alkoxy)propylene radical; R₃ represents a C₁₋₈ alkylradical; R₄ is selected from hydrogen and C₁₋₈ alkyl; R is selected fromhydrogen, C₁₋₈ alkyl, C₃₋₆ cycloalkyl, benzyl and phenyl optionallysubstituted with one or more substituents, which may be identical ordifferent, selected from halogen, lower C₁₋₄ alkyl, lower C₁₋₄ alkoxyand nitro; as well as the N-oxide derivative thereof and apharmaceutically acceptable salt thereof.
 8. An aminoalkoxyphenylderivative according to claim 7 in which R represents an isopropyl orcyclopropyl group.
 9. A pharmaceutical or veterinary composition for usein the treatment of angina pectoris, hypertension, arrhythmia, andcerebral vascular insufficiency, comprising an effective amount fortreating angina pectoris, hypertension, arrhythmia or cerebral vascularinsufficiency of at least one aminoalkoxyphenyl compound according toclaim
 1. 10. A method of treating angina pectoris, hypertension,arrhythmia and cerebral vascular insufficiency in a host in need of suchtreatment comprising the administration to the host of an effective doseof an aminoalkoxyphenyl compound according to claim
 1. 11. Anaminoalkoxyphenyl derivative of formula: ##STR176## in which: B isselected from --S--, --SO-- and --SO₁ --;R is selected from hydrogen,linear- or branched-alkyl, cycloalkyl containing at most 6 carbon atomsand phenyl which is unsubstituted or substituted with one or moresubstituents, which may be identical or different, selected fromhalogen, lower C₁₋₄ alkyl, lower C₁₋₄ alkoxy and nitro; R₁ and R₂, whichare identical or different, are selected from hydrogen, methyl, ethyland halogen; A is selected from linear- or branched-alkylene having from2 to 5 carbon atoms and 2-hydroxypropylene; R₃ is selected from linear-or branched-C₁₋₈ alkyl and a radical of formula Alk-R₅, in which Alkdenotes a single bond or a linear- or branched-alkylene radical havingfrom 1 to 5 carbon atoms, and R₅ is selected from pyridyl, phenyl,2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl and phenylsubstituted with one or more substituents which may be identical ordifferent, selected from halogen, lower C₁₋₄ -alkyl and lower C₁₋₄alkoxy; R₄ is selected from hydrogen and alkyl; as well as apharmaceutically acceptable salt of this derivative.
 12. Anaminoalkoxyphenyl compound of formula: ##STR177## in which: B isselected from --S--, --SO-- and --SO₁ --;R is selected from hydrogen,methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertbutyl,1-methyl-propyl, n-pentyl, neopentyl, phenyl, monofluoro-, monochloro-or monobromophenyl, difluoro-, dichloro-, or dibromophenyl, monomethyl-or dimethylphenyl, monomethoxy or dimethoxyphenyl, nitrophenyl andmethylphenyl substituted with a halogen atom; R₁ and R₂, which areidentical or different, are selected from hydrogen, chlorine, bromine,iodine and methyl; A is selected from 1,2-ethylene, 1,3-propylene,2-methyl-1,3-propylene, 1,4-tetramethylene, 1,5-pentamethylene and2-hydroxypropylene; R₃ is selected from methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl, 1-methylpropyl, n-pentyl,n-hexyl, n-heptyl, n-octyl, phenyl, benzyl, phenethyl, methoxyphenethyl,dimethoxyphenethyl, dimethylphenethyl, dimethoxyphenyl, dimethoxybenzyland pyridyl ethyl or phenethyl substituted in the aromatic portion withmethyl and methoxy radicals; R₄ is selected from hydrogen, methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertbutyl, n-pentyl,neopentyl, n-hexyl, n-heptyl and n-octyl; as well as a pharmaceuticallyacceptable salt of this derivative.
 13. An aminoalkoxyphenyl compoundaccording to claim 11 wherein B represents a --SO₂ -- group.
 14. Anaminoalkoxyphenyl compound according to claim 11 wherein R₃ represents a3,4-dimethoxyphenyl, 3,4-dimethoxybenzyl or 3,4-dimethoxyphenethylradical.
 15. An aminoalkoxyphenyl compound according to claim 11 whereinthe pharmaceutically acceptable salt is the hydrochloride.
 16. Apharmaceutical or veterinary composition for use in the treatment ofangina pectoris, hypertension, arrhythmia, and cerebral vascularinsufficiency, comprising an effective amount for treating anginapectoris, hypertension, arrhythmia and cerebral vascular insufficiencyof at least one aminoalkoxyphenyl compound according to claim 11 incombination with a pharmaceutical vehicle or a suitable excipient.
 17. Apharmaceutical or veterinary composition for use in the treatment ofangina pectoris, hypertension, arrhythmia, and cerebral vascularinsufficiency, comprising an effective amount for treating anginapectoris, hypertension, arrhythmia and cerebral vascular insufficiencyof at least one aminoalkoxyphenyl compound according to claim 13 incombination with a pharmaceutical vehicle or a suitable excipient.
 18. Apharmaceutical or veterinary composition according to claim 17 for thetreatment of pathological syndromes of the cardiovascular system,containing from 50 mg to 500 mg of the said aminoalkoxyphenyl compound.